ES2550485T3 - Neutral endopeptidase inhibitor intermediates and method of their preparation - Google Patents

Abstract

A process for the preparation of a compound of formula (1), or a salt thereof, ** Formula ** wherein R1 is hydrogen or a nitrogen protecting group; said process comprising the steps of (i) preparing a compound of formula (4), or a salt thereof, ** Formula ** wherein: R1 is hydrogen or a nitrogen protecting group; and R4 is selected from alkyl, aryl, and aryl-alkyl; reacting a compound of the formula (3), or a salt thereof: ** Formula ** wherein R1 is hydrogen or a nitrogen protecting group; first with a base and then with a compound of the formula R4COY, where R4 is selected from alkyl, aryl and aryl-alkyl, and Y is halogen or -OR ', where R' is selected from alkyl, aryl and aryl-alkyl, to obtain the compound of the formula (4), or a salt thereof; and (ii) reacting the compound of the formula (4) obtained, or a salt thereof, with a base and formaldehyde, optionally in the presence of a phase transfer catalyst, to obtain the compound of the formula (1), or a salt of it.

Description

E11734379

10-19-2015

DESCRIPTION

Neutral endopeptidase inhibitor intermediates and method of their preparation

5 The invention relates to a new process to produce useful intermediates for the preparation of neutral endopeptidase (NEP) inhibitors or pro-drugs thereof, in particular neutral endopeptidase (NEP) inhibitors comprising a base structure of γ-amino-δ-biphenyl-α-methyl-alkanoic acid or acid ester.

Endogenous atrial natriuretic peptides (ANP), also known as natriuretic factors

Headphones (ANF) have diuretic, natriuretic, and vaso-relaxant functions in mammals. Natural atrial natriuretic factor (ANF) peptides are metabolically inactivated, in particular by a degrading enzyme that has been recognized to correspond to the neutral endopeptidase enzyme (NEP, EC 3,4,24,11), also responsible, for example, for the metabolic inactivation of enkephalins.

15 Biaryl substituted phosphonic acid derivatives are known in the art and are useful as inhibitors of neutral endopeptidase (NEP), for example, as inhibitors of the enzyme that degrades atrial natriuretic factor (ANF) in mammals. , to prolong and enhance the diuretic, natriuretic and vasodilator properties of atrial natriuretic factor (ANF) in mammals, by inhibiting its degradation to less active metabolites. Therefore, neutral endopeptidase (NEP) inhibitors are in

20 particularly useful for the treatment of conditions and disorders that respond to inhibition of neutral endopeptidase (EC 3,4,24,11), in particular of cardiovascular disorders, such as hypertension, renal failure including edema and salt retention, pulmonary edema and congestive heart failure.

Processes for the preparation of neutral endopeptidase (NEP) inhibitors are known. The Patent of

25 United States of America Number US 5 217 996 describes biaryl substituted 4-amino-butyric acid amide derivatives, which are useful as inhibitors of neutral endopeptidase (NEP), for example, as inhibitors of the enzyme that degrades atrial natriuretic factor (ANF) in mammals. United States Patent Number US 5 217 996 discloses the preparation of the acid ethyl ester N- (3-carboxy-1-oxo-propyl) - (4S) - (p-phenyl-phenyl-methyl) - 4-amino- (2R) -methyl-butanoic. In the preparation of the compound

In the aforementioned, N-tert-butoxy-carbonyl- (4R) - (p-phenyl-phenyl-methyl) -4-amino-2-methyl-2-butenoic acid ethyl ester is hydrogenated in the presence of palladium on carbon. International Publication Number WO2009 / 090251 refers to a reaction route for the preparation of the N-tertbutoxy-carbonyl- (4S) - (p-phenyl-phenylmethyl) -4-amino-2-methyl acid ethyl ester compound. -butanoic, or a salt thereof, where an alternative hydrogenation step provides better diastereoselectivity, compared to that obtained in the United States Patent

35 States of North America Number US 5 217 996. A key intermediate of the route described in International Publication Number WO2009 / 090251, is a compound of formula (1):

image 1

R1

(1)

40 or a salt thereof, wherein R1 is hydrogen or a nitrogen protecting group. Section B of International Publication Number WO2009 / 090251 discloses different methods for the preparation of a compound of formula (1). All these methods use as starting material, a compound of formula (2), or a salt thereof:

E11734379

10-19-2015

R6

image2

R1

(2)

wherein R1 is hydrogen or a nitrogen protecting group, and R6 and R7 are, independently, an alkyl group, an aryl group, an aryl-alkyl group, a cycloalkyl group, or together, R6 and R7 form a cycle, together with the atom of

5 nitrogen to which they are attached, the ring of which may be saturated or unsaturated, and may optionally contain one or more heteroatoms, such as a nitrogen, oxygen or sulfur atom, wherein the ring contains 3 to 8, such as 4 to 7 ring atoms.

These different methods for preparing a compound of formula (1) from a compound of formula (2) of International Publication Number WO2009 / 090251 comprise, for example

(a) the direct transformation of the enamine of formula (2) into the exo-methylene group of formula (1) using a reducing agent such as borohydrides and metal hydrides as described in section B.3.1 of the International Publication WO2009 / 090251;

(B) the transformation of the enamine of formula (2) -through the free enol form -to the exo-methylene group of formula (1) as described in sections B.1 (treatment with an acid) / B .3,2 (treatment with a reducing agent) and section B.2.1 (treatment with a reducing agent at neutral or alkaline pH) of International Publication Number WO2009 / 090251.

As described in section A of International Publication Number WO2009 / 090251, the preparation of a compound of formula (2), or a salt thereof, comprises reacting a compound of formula (3), or a get out of it:

image3

R1

(3)

wherein R1 is hydrogen or a nitrogen protecting group, with an amine of formula (13), (14) or (15), or mixtures thereof:

image4 R6 R7 image5 R6 R7 NN image6 R6 R7 R6 R6 R6 R8 NN image7 N image8 NO R8 R8 R7 R7 R7 OO

(13), (14),

(fifteen)

Wherein each R6 and each R7 are, independently, an alkyl group, an aryl group, an aryl-alkyl group, a cycloalkyl group, or together, R6 and R7 form a cycle, together with the nitrogen atom with which they are linked, whose ring may be saturated or unsaturated, and may optionally contain one or more heteroatoms, such as a nitrogen, oxygen or sulfur atom, wherein the ring contains 3 to 8, such as 4 to 7 ring atoms, and

Each R8 is independently an alkyl group, an aryl group or an aryl-alkyl group, to obtain the compound

E11734379

10-19-2015

of formula (2).

The large-scale preparation of an amine of the formula (13), (14) or (15) is a difficult process, which leads to mixtures thereof, where the proportion of each amine can change from one batch to another. . The reactivity of the amines of the formula (13), (14) or (15) is different. In accordance with the foregoing, in view of the fact that the preparation of an amine of formula (13), (14) or (15) results in variable mixtures thereof, with different reactivity profiles, the scale-up Commercialization of a compound of the formula (1) by means of a compound of the formula (2) is problematic. Accordingly, there is a need for the development of an alternative synthesis of the compounds of formula (1), as described above, which can be used

10 for the commercial scale production thereof, and avoiding the aforementioned drawbacks of the prior art process. Consequently, the object of the present invention is to provide a new process for the preparation of the compound of formula (1), which may be suitable for its preparation on a commercial scale.

15 The new process, according to the present invention, to produce a compound according to formula (1),

or a salt thereof, as defined herein, is summarized in Scheme 1.

image9

20 Scheme 1

That is, a compound of the formula (3), as described herein, is converted to a compound of the formula (1), or a salt thereof, wherein R1 is hydrogen or a nitrogen protecting group, according to a method described in Section A.

The preparation of a compound of formula (3), as described herein, is described, for example, in Method 1 of Subsection C-1 of International Publication Number WO2008 / 083967.

International Publication Number WO2008 / 083967 describes a process for converting a compound of the

Formula (1), as described herein, into a neutral endopeptidase (NEP) inhibitor or a pro-drug thereof. Accordingly, a compound of formula (1) can be used as an intermediate in the preparation of neutral endopeptidase (NEP) inhibitors, or pro-drugs thereof, in particular neutral endopeptidase inhibitors. (NEP) comprising a base structure of γ-amino-δ-biphenyl-α-methyl-alkanoic acid or of acid ester, preferably of the alkyl ester of the acid N- (3-carboxyl-1-oxo-propyl) - (4S ) - (p

35 phenyl-phenyl-methyl) -4-amino- (2R) -methyl-butanoic acid, such as N- (3-carboxyl-1-oxo-propyl) - (4S) - (p-phenylphenyl) -methyl) -4-amino- (2R) -methyl-butanoic.

The invention, as a whole, comprises the following sections:

40 Section A: Preparation methods for the compound of formula (1). Section B: Novel and Inventive Compounds. Section C: Examples.

It is noted that, in the present application, usually the explanations made in a section are also

45 applicable for other sections, unless otherwise stated. For example, the explanations for the residue R4 in formula (4) given in Section A also apply if formula (4) is presented in Section B, unless otherwise reported. When referring to the compounds described in the present invention, it is understood that the salts thereof are also being referred to. Depending on the choice of starting materials and procedures, the compounds may be present in the form

50 of one of the possible isomers or as mixtures thereof, for example, as the pure optical isomers, or as mixtures of isomers, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.

In a further embodiment, the present invention also relates to a process for the preparation of the ethyl ester

55 from N- (3-carboxyl-1-oxo-propyl) - (4S) - (p-phenyl-phenyl-methyl) -4-amino- (2R) -methyl-butanoic acid, or a salt thereof, which comprises the preparation of the compound of formula (4), or a salt thereof, as defined above.

E11734379

10-19-2015

Section A: Preparation of a compound of formula (1)

Section A.1: Synthesis of a compound of formula (4)

5 This section refers to a process for the manufacture of a compound of formula (1), as defined herein, wherein the conversion of a compound of formula (3), as defined herein, into The aforementioned compound of formula (1), takes place stepwise, that is, in two separate steps with isolation of the intermediate species of formula (4), as defined herein.

In one embodiment, the present invention relates to a process for the preparation of a compound of formula (4), or a salt thereof:

image10

Wherein: R1 is hydrogen or a nitrogen protecting group; and R4 is selected from alkyl, aryl, and aryl-alkyl; Preferably wherein the compound of formula (4) is of formula (4a):

image11

R1 (4th)

wherein R1 and R4 are as defined for the compound of formula (4); this process comprising reacting a compound of formula (3), or a salt thereof:

image12

R1

(3)

wherein R1 is hydrogen or a nitrogen protecting group; Preferably wherein the compound of formula (3) is of formula (3a):

E11734379

10-19-2015

image13

R1

(3rd)

wherein R1 is as defined for the compound of formula (3); first with a base, and then with a compound of the formula R4COY, where Y is halogen or -OR ', and where R4 and R' are independently selected from alkyl, aryl, and aryl-alkyl, to obtain the compound of the formula (4), or a salt thereof.

In another embodiment, the present invention refers to a process of the present invention that comprises a first step for the preparation of a compound of formula (4), or a salt thereof:

image14

wherein: R1 is hydrogen or a nitrogen protecting group; and R4 is hydroxyl; preferably wherein the compound of formula (4) is of formula (4a):

image15

R1

20 (4th)

wherein R1 and R4 are as defined for the compound of formula (4); comprising this process: reacting a compound of formula (3), or a salt thereof:

25

E11734379

10-19-2015

image16

R1

(3)

wherein R1 is hydrogen or a nitrogen protecting group; preferably wherein the compound of formula (3) is of formula (3a):

image17

R1

(3rd)

wherein R1 is as defined for the compound of formula (3); first with a base, and then with a compound of the formula CO2 to obtain the compound of the formula (4), or a salt thereof.

Suitable bases for the conversion of a compound of the formula (3), preferably of the formula (3a), as described herein, to a compound of the formula (4), preferably of the formula (4a), such as described herein include:

Metal hydrides, such as alkali metal hydrides (for example sodium or potassium hydride); -alkali metal alkoxides (eg sodium methoxide, potassium tert-butoxide); -amines, such as 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU); -a base of the formula MRa, where M is an alkali metal (e.g. lithium, sodium, potassium), and Ra is alkyl

20 or aryl, for example MRa is methyl lithium, n-butyllithium, sec-butyllithium, tert-butyl lithium, or phenyllithium;

-a base of the formula RcRdNM, where Rc and Rd are independently selected from alkyl, cycloalkyl, heterocyclyl or silyl, and M is an alkali metal (eg lithium, sodium, potassium), eg RcRdNM is bis Lithium - (trimethylsilyl) -amide (LHMDS), sodium bis- (trimethylsilyl) -amide (NaHMDS), potassium bis- (trimethylsilyl) -amide (KHMDS), lithium di-isopropylamide ( LDA) or potassium di-isopropylamide; or

25 -mixtures thereof.

In one embodiment, the base is an amine, such as triethylamine, di-isopropyl-ethyl-amine, optionally in the presence of an additive selected from an alkaline earth metal halide, such as magnesium chloride, magnesium bromide, and magnesium iodide.

Preferably, the base is lithium bis- (trimethylsilyl) -amide (LHMDS), lithium di-isopropylamide, or sodium hydride, more preferably lithium bis- (trimethylsilyl) -amide (LHMDS ).

Section A.2: Synthesis of a compound of the formula (1) from a compound of the formula (4)

The process as claimed in the present invention comprises, in a second stage, a process for the preparation of a compound of formula (1), or a salt thereof:

E11734379

10-19-2015

image18

R1

(1)

wherein R1 is hydrogen or a nitrogen protecting group; preferably wherein the compound of formula (1) is of formula (1a):

image19

R1

(1a)

wherein R1 is as defined for the compound of formula (1); understanding this process:

10 reacting a compound of the formula (4), or a salt thereof:

image20

where: 15

R1 is hydrogen or a nitrogen protecting group; and

R4 is selected from hydroxyl, alkyl, aryl, and aryl-alkyl;

preferably wherein the compound of formula (4) is of formula (4a):

image21

R1 (4th)

wherein R1 and R4 are as defined for the compound of formula (4);

with a base and formaldehyde, optionally in the presence of a phase transfer catalyst, to obtain the compound of formula (1), or a salt thereof.

E11734379

10-19-2015

Suitable bases for the conversion of a compound of the formula (4), preferably of the formula (4a), as described herein, to a compound of the formula (1), preferably of the formula (1a), such as described herein, include metal hydrides, such as alkali metal hydrides (eg, sodium or potassium hydride), alkali metal alkoxides (eg, sodium methoxide, potassium tert-butoxide), an amine, such as di-isopropyl-ethyl-amine, triethylamine, morpholine, or 1,8-diaza-bicyclo- [5,4.0] -undec-7-ene, an inorganic base, such as an alkali metal carbonate, such as potassium carbonate, a base of the formula MRa, where M is an alkali metal (eg, sodium lithium, potassium), and Ra is alkyl or aryl, eg MRa is methyllithium, n-butyllithium, sec- butyllithium, tert-butyllithium or phenyllithium, a base of the formula RcRdNM, where Rc and Rd are independently selected from alkyl, cycloalkyl, heterocyl clyl or silyl, and M is an alkali metal (for

10 example, lithium sodium, potassium), for example RcRdNM is lithium bis- (trimethylsilyl) -amide (LHMDS), sodium bis- (trimethylsilyl) amide (NaHMDS), bis- (trimethylsilyl) potassium amide (KHMDS), lithium di-isopropylamide (LDA) or potassium diisopropylamide; or mixtures thereof.

In a preferred embodiment, the conversion of a compound of formula (4), preferably wherein the

A compound of the formula (4) is of the formula (4a), in a compound of the formula (1), as described above, it takes place in the presence of a base and an alkali metal salt, such as LiCl. More preferably, this conversion takes place in the presence of a base, an alkali metal salt, such as LiCl, and a drying agent, such as molecular sieves, an alkali metal sulfate (eg, sodium sulfate), or a sulfate. alkaline earth metal (eg magnesium sulfate).

twenty

Section A.3: Synthesis of a compound of the formula (1) from a compound of the formula (3)

Therefore, in a first aspect, the present invention relates to a process for the preparation of a compound of formula (1), or a salt thereof:

25

image22

R1

(1)

wherein R1 is hydrogen or a nitrogen protecting group; preferably wherein the compound of formula (1) is of formula (1a):

image23

R1

(1a)

wherein R1 is as defined for the compound of formula (1); understanding this process the steps of:

(i) prepare a compound of formula (4), or a salt thereof:

E11734379

10-19-2015

image24

wherein: R1 is hydrogen or a nitrogen protecting group; and R4 is selected from alkyl, aryl, and aryl-alkyl; preferably wherein the compound of formula (4) is of formula (4a):

image25

R1

10 (4th)

wherein R1 and R4 are as defined for the compound of formula (4); by reacting a compound of formula (3), or a salt thereof:

image26

R1

15 (3)

wherein R1 is hydrogen or a nitrogen protecting group;

preferably wherein the compound of formula (3) is of formula (3a):

image27

R1

20 (3a) E11734379

10-19-2015

wherein R1 is as defined for the compound of formula (3); first with a base, and then with a compound of the formula R4COY, where Y is halogen or -OR ', and where R4 and R' are independently selected from alkyl, aryl, and aryl-alkyl, to obtain the compound of formula (4), or a salt thereof; and

(ii) reacting the compound of formula (4), or a salt thereof:

image28

where:

R1 is hydrogen or a nitrogen protecting group; and R4 is selected from alkyl, aryl, and aryl-alkyl;

preferably wherein the compound of formula (4) is of formula (4a):

image29

R1 (4th)

wherein R1 and R4 are as defined for the compound of formula (4); with a base and formaldehyde, optionally in the presence of a phase transfer catalyst, to obtain the compound of formula 20 (1), or a salt thereof.

In another aspect, the present invention relates to the above process, for converting the compound of the formula (3) into the compound of the formula (1), wherein steps i) and ii) take place by means of a process of a container, and therefore without isolation and / or purification of the compound of formula (4).

In a second aspect, the present invention relates to a process for the preparation of a compound of formula (1), or a salt thereof:

image30

R1

(1)

wherein R1 is hydrogen or a nitrogen protecting group; preferably wherein the compound of formula (1) is of formula (1a):

E11734379

10-19-2015

image31

R1

(1a)

wherein R1 is as defined for the compound of formula (1); understanding this process the steps of:

(i) prepare a compound of formula (4), or a salt thereof:

image32

Where: R1 is hydrogen or a nitrogen protecting group; and R4 is hydroxyl; 15 preferably wherein the compound of formula (4) is of formula (4a):

image33

R1 (4th)

wherein R1 and R4 are as defined for the compound of formula (4); 20 by reacting a compound of formula (3), or a salt thereof:

image34

R1

(3)

E11734379

10-19-2015

wherein R1 is hydrogen or a nitrogen protecting group; preferably wherein the compound of formula (3) is of formula (3a):

image35

R1

(3rd)

Wherein R1 is as defined for the compound of formula (3); first with a base, and then with a compound of the formula CO2 to obtain the compound of the formula (4), or a salt thereof; and

(ii) reacting the compound of formula (4), or a salt thereof:

image36

wherein: R1 is hydrogen or a nitrogen protecting group; and R4 is hydroxyl; preferably wherein the compound of formula (4) is of formula (4a):

image37

R1

20 (4th)

wherein R1 and R4 are as defined for the compound of formula (4); with a base and formaldehyde, optionally in the presence of a phase transfer catalyst, to obtain the compound of formula (1), or a salt thereof.

In still another aspect, the present invention relates to the above process, for converting the compound of the formula (3) into the compound of the formula (1), wherein steps i) and ii) take place by means of a one-pot process, and therefore without isolation and / or purification of the compound of formula (4).

30 The bases suitable for step (i), in the previous embodiments, are as those described in section

A.1.

The bases suitable for step (ii), in the previous embodiments, are as those described in section

A.2. Preferably, step (ii), in the previous embodiments, takes place in the presence of a base and a salt of

E11734379

10-19-2015

alkali metal, such as LiCl. More preferably, this conversion takes place in the presence of a base, an alkali metal salt, such as LiCl, and a drying agent, such as molecular sieves, an alkali metal sulfate (eg, sodium sulfate), or a sulfate. alkaline earth metal (eg magnesium sulfate).

Section b:

A compound of the formula (4), or a salt thereof:

image38

10 where:

R1 is hydrogen or a nitrogen protecting group selected from t-Tuboxycarbonyl, benzoyl, styryl, 1-butenyl, benzyl, p-methoxybenzyl, and pyrrolidinylmethyl; and

R4 is selected from t-butyl, methyl, isopropyl, and phenyl;

preferably wherein the compound of formula (4) is of formula (4a):

image39

R1

(4a) wherein R1 and R4 are as defined for the compound of formula (4).

General terms:

25 The general definitions used above and below, unless defined differently, have the following meanings:

The term "nitrogen protecting group" comprises any group that is capable of reversibly protecting a nitrogen functionality, preferably an amine and / or amide functionality. Preferably, the nitrogen protecting group is an amine protecting group and / or an amide protecting group. Suitable nitrogen protecting groups are conventionally used in peptide chemistry, and are described, for example, in the relevant chapters of standard reference works, such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis', Fourth Edition, Wiley, New Jersey, 2007, in" The

35 Peptides "; Volume 3 (Editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, and in" Methoden der organischen Chemie "(Methods of organic chemistry), Houben Weyl, 4th Edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974.

Preferred nitrogen protecting groups broadly comprise:

Unsubstituted or substituted alkyl of 1 to 6 carbon atoms, preferably alkyl of 1 to 4 carbon atoms, more preferably alkyl of 1 to 2 carbon atoms, more preferably alkyl of 1 carbon atoms, alkenyl of 2 to 4 carbon atoms unsubstituted or substituted carbon, wherein alkyl of 1 to 6 carbon atoms, and alkenyl of 2 to 4 carbon atoms, is optionally mono-, di- or tri-substituted by trialkyl-silyl

C 1 to 7 alkoxy (for example, trimethylsilyl ethoxy), aryl, preferably phenyl, or a heterocyclic group, preferably pyrrolidinyl, wherein the aryl ring or heterocyclic group is unsubstituted or

E11734379

10-19-2015

substituted by one or more, eg two or three residues, eg selected from the group consisting of C 1 to 7 alkyl, hydroxyl, C 1 to 7 alkoxy, 2 to 8 alkanoyloxy carbon, halogen, nitro, cyano, and CF3 atoms; aryl-C 1 -C 2 -alkoxy-carbonyl (preferably phenyl-C 1 -C 2 -alkoxy-carbonyl, eg benzyloxy-carbonyl);

5 alkenyloxy of 1 to 10 carbon atoms; C 1 -C 6 alkylcarbonyl (eg, acetyl, or pivaloyl); aryl of 6 to 10 carbon atoms-carbonyl; C 1 -C 6 alkoxycarbonyl (eg, tert-butoxycarbonyl); aryl of 6 to 10 carbon atoms-alkoxy of 1 to 6 carbon atoms-carbonyl; allyl or cinnamyl; sulfonyl, or sulfenyl; a succinimidyl, silyl group, eg, triarylsilyl or trialkylsilyl (eg, triethylsilyl).

Examples of preferred nitrogen protecting groups are acetyl, benzyl, cumyl, benzhydryl, trityl, benzyloxy-carbonyl (Cbz), 9-fluorenyl-methyloxy-carbonyl (Fmoc), benzyloxy-methyl (BOM), pivaloyloxy-methyl (POM ), trichloroethoxycarbonyl (Troc), 1-adamantyloxycarbonyl (Adoc), allyl, allyloxycarbonyl, trimethylsilyl, tertbutyldimethylsilyl, triethylsilyl (TES), triisopropylsilyl, trimethylsilyl -ethoxy-methyl (SEM), tert-butoxy-carbonyl (BOC), tert-butyl, 1-methyl

1,1-dimethyl-benzyl, (phenyl) -methyl-benzene, pyrrolidinyl, and pivaloyl. The most preferred nitrogen protecting groups are acetyl, benzyl, benzyloxycarbonyl (Cbz), triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), tertbutoxycarbonyl (BOC), pyrrolidinylmethyl, and pivaloyl. .

Examples of highly preferred nitrogen protecting groups are tert-butoxycarbonyl (BOC), benzoyl, styryl, 1-butenyl, benzyl, p-methoxy-benzyl (PMB), and pyrrolidinyl-methyl.

Silyl, as used herein, refers to a group according to the formula -SiR11R12R13, wherein R11, R12 and R13 are, independently of one another, alkyl or aryl. Preferred examples for R11, R12, and R13 are methyl, ethyl, isopropyl, tert-butyl, phenyl, or phenyl-C 1 -C 4 -alkyl.

25 Alkyl is defined as a radical or as part of a radical, and is a straight or branched carbon chain (one or, if desired and possible, more times), and is especially alkyl of 1 to 7 carbon atoms , preferably alkyl of 1 to 4 carbon atoms.

The term "C1-C7" defines a fraction with up to and including maximum 7, especially up to and including maximum 4 carbon atoms, this fraction being branched chain (one or more times) or straight chain, and being linked by means of a terminal or non-terminal carbon atom.

Cycloalkyl is, for example, cycloalkyl of 3 to 7 carbon atoms, and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

Alkoxy is, for example, alkoxy of 1 to 7 carbon atoms, and is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and also includes the corresponding radicals of pentyloxy, hexyloxy, and heptyloxy. C 1 to 4 alkoxy is preferred.

Alkanoyl is, for example, alkanoyl of 2 to 8 carbon atoms and is, for example, acetyl [-C (= O) Me], propionyl, butyryl, isobutyryl or pivaloyl. Alkanoyl of 2 to 5 carbon atoms, especially acetyl, is preferred.

Halo or halogen is preferably fluorine, chlorine, bromine or iodine, most preferably chlorine, bromine, or iodine.

Halo-alkyl is, for example, halo-alkyl of 1 to 7 carbon atoms, and is in particular halo-alkyl of 1 to 4 carbon atoms, such as trifluoromethyl, 1,1,2-trifluoro-2 -chloro-ethyl, or chloro-methyl. The preferred halo-C 1-7 -alkyl is trifluoromethyl.

Alkenyl may be straight or branched alkyl containing one double bond and preferably comprising 2 to 12 carbon atoms, with 2 to 10 carbon atoms being especially preferred. In particular a linear alkenyl of 2 to 4 carbon atoms is preferred. Some examples of alkyl groups are ethyl and the propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, and eicosyl isomers, each of which contains one double bond. Allyl is especially preferred.

55 Alkylene is a bivalent radical derived from alkyl of 1 to 7 carbon atoms, and is especially alkylene of 2 to 7 carbon atoms or alkylene of 2 to 7 carbon atoms and, optionally, can be interrupted by one or plus, for example, up to three, O, NR14, or S, where R14 is alkyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from, for example, alkyl of 1 to 7 atoms carbon, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, or alkoxy of 1 to 7 carbon atoms.

Alkenylene is a bivalent radical derived from alkenyl of 2 to 7 carbon atoms, and can be interrupted by one or more, for example up to three, O, NR14 or S, where R14 is alkyl, and is unsubstituted or

Substituted by one or more, for example, up to three substituents preferably independently selected from the aforementioned substituents for alkylene.

E11734379

10-19-2015

Aryl which is a radical or part of a radical is, for example, aryl of 6 to 10 carbon atoms, and is preferably a mono- or poly-cyclic aryl moiety, especially monocyclic, bicyclic, or tricyclic with 6 to 10 carbon atoms, preferably phenyl, and which may be unsubstituted or substituted by one or more substituents independently selected from, for example, alkyl of 1 to 7 carbon atoms,

5 alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, or alkoxy of 1 to 7 carbon atoms.

The term "aryl-alkyl" refers to aryl-alkyl of 1 to 7 carbon atoms, where aryl is as defined herein, and is, for example, benzyl.

The term "carboxyl" refers to -CO2H.

Aryloxy refers to an Aryl-O- where aryl is as defined above.

Unsubstituted or substituted heterocyclyl is a mono- or poly-cyclic ring system, preferably mono-, bi-or

Tricyclic, more preferably monocyclic, unsaturated, partially saturated, saturated or aromatic, with preferably 3 to 14 (more preferably 5 to 14) ring atoms, and with one or more, preferably one to four heteroatoms independently selected from nitrogen, oxygen, sulfur, S (= O) -or S - (= O) 2, and is unsubstituted or substituted by one or more, for example, up to three preferably independently selected substituents from preferred substituents selected from the group that consists of halogen, C 1 to 7 alkyl, C 1 to 7 halo-alkyl, C 1 to 7 alkoxy, C 1 to 7 halo-alkoxy, such as trifluoro-methoxy and alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms. When heterocyclyl is an aromatic ring system, it is also referred to as heteroaryl.

Acetyl is -C (= O) -alkyl of 1 to 7 carbon atoms, preferably -C (= O) Me.

Sulfonyl is C 1 to 7 alkyl sulfonyl, such as methyl sulfonyl (unsubstituted or substituted), phenyl- or naphthyl C 1 to 7 alkyl sulfonyl (unsubstituted or substituted), such as phenyl methane -sulfonyl, or phenyl- or naphthylsulfonyl (unsubstituted or substituted); wherein, if more than one substituent is present, for example one to three substituents, the substituents are independently selected from cyano, halogen, halo-C 1 -C 7 -alkyl, 1-to-7 halo-alkyloxy carbon atoms, and alkyloxy of 1 to 7 carbon atoms. C 1-7 alkyl sulfonyl, such as methyl sulfonyl, and (phenyl- or naphthyl) C 1-7 alkyl sulfonyl, such as phenyl methanesulfonyl, are especially preferred.

35 Sulfenyl is aryl of 6 to 10 carbon atoms-alkyl of 1 to 7 carbon atoms-sulfenyl (unsubstituted or substituted), or aryl of 6 to 10 carbon atoms-sulfenyl (unsubstituted or substituted), where, if it is Presenting more than one substituent, eg, one to four substituents, the substituents are independently selected from nitro, halogen, halo-C 1 -C 7 alkyl, and C 1 -C 7 alkyloxy.

The term "chiral" refers to molecules that have the property of not being able to overlap on their mirror image partner, while the term "achiral" refers to molecules that can overlap on their mirror image partner.

The term "tautomer" refers in particular to the enol tautomer of the pyrrolidin-2-one moiety of

45 compounds of the present invention. Additionally, the term "tautomer" also refers in particular to the aldehyde tautomer of the compounds of the present invention, for example the compounds of formula (6), wherein these compounds may exist in either an enol or aldehyde, or mixtures thereof.

In the formulas of the present application, the term " image40 "on a C-sp3 image41 represents a covalent bond, where the stereochemistry of the bond is not defined. This means that the term "" on a C-sp3 comprises an (S) configuration as well as an (R) configuration of the respective chiral center. Additionally, mixtures are also encompassed, eg, mixtures of enantiomers, such as racemates, are encompassed in the present invention.

55 In the formulas of the present application, the term " image42 "on a C-sp2 represents a covalent bond, where the stereochemistry or geometry of the bond is not defined. This means that the term" image43 "on a Csp2 comprises a cis (Z) configuration as well as a trans (E) configuration of the respective double bond. Additionally, mixtures are also encompassed, eg mixtures of double bond isomers, are encompassed in the present invention.

The compounds of the present invention may possess one or more asymmetric centers. Preferred absolute configurations are as specified herein in a specific manner.

65 In the formulas of the present application, the term "

image44 "on a C-sp3 indicates the absolute stereochemistry, either (R)

or (S).

E11734379

10-19-2015

In the formulas of the present application, the term "

image45 "on a C-sp3 indicates the absolute stereochemistry, either

(R) or (S).

In the formulas of the present application, the term "

"Indicates a Csp3-Csp3 bond or a Csp25 Csp2 bond.

The salts are especially the pharmaceutically acceptable salts or, in general terms, the salts of any of the intermediates mentioned herein, where the salts are not excluded for chemical reasons that will be readily understood by the skilled person. They can be formed where salt-forming groups are present,

10 such as basic or acidic groups, which can exist in an at least partially dissociated form, for example in a pH range of 4 to 10 in aqueous solutions, or can be isolated especially in a solid, especially crystalline form.

These salts are formed, for example, as acid addition salts, preferably with organic acids or

Inorganic compounds, from the compounds or any of the intermediates mentioned herein, with a basic nitrogen atom (eg imino or amino), especially the pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulphonic or sulphamic acids, for example acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid,

20 citric acid, the amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxy-maleic acid, methyl-maleic acid, benzoic acid, methane- or ethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid , 2-naphthalene sulfonic acid, 1,5-naphthalene disulfonic acid, N-cyclohexyl-sulfamic acid, N-methyl-, Netyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as acid ascorbic.

In the presence of negatively charged radicals, such as carboxyl or sulfo, salts with bases can also be formed, for example, the metal or ammonium salts, such as the alkali metal or alkaline earth metal salts, for example, the sodium, potassium, magnesium or calcium salts, or the ammonium salts with ammonia or with suitable organic amines, such as tertiary monoamines, for example triethylamine or tri- (2-hydroxyethyl) amine, or heterocyclic bases, for example, N-ethyl-piperidine or N, N'-dimethyl-piperazine.

When a basic group and an acid group are present in the same molecule, any of the intermediates mentioned herein can also form internal salts.

For isolation or purification purposes, of any of the intermediates mentioned herein, it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates.

In view of the close relationship between compounds and intermediates in free form and in the form of their salts, including salts that can be used as intermediates, for example, in the purification or identification of compounds or salts of themselves, any reference to "compounds", "starting materials" and

40 "intermediates" hereinafter and hereinafter, should be understood to refer also to one or more salts thereof, or to a mixture of a corresponding free compound, intermediate or starting material, and one or more salts of the same, each of which is intended to also include any solvate or a salt of any or more thereof, as appropriate and convenient, and if not explicitly mentioned otherwise. Different crystal forms can be obtained, and then , are also included.

When the plural form is used for compounds, starting materials, intermediates, salts, pharmaceutical preparations, diseases, disorders, and the like, this is intended to mean one (preferred) or more compounds, salts, pharmaceutical preparations, diseases, disorders, or the like. individual; when the singular is used

or the indefinite article ("one", "one"), this is not intended to exclude the plural, but preferably only means "one".

Any of the lactams according to the present invention, or the salts thereof, where R1 is hydrogen, can be converted to a corresponding protected lactam, or a salt thereof, where R1 is a nitrogen protecting group , as defined above, in accordance with conventional methods of organic chemistry known in the art, and in particular reference is made to the conventional nitrogen protecting group methods described in JFW McOmie, "Protective Groups in Organic Chemistry" , Plenum Press, London and New York 1973, in PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis', Fourth Edition, Wiley, New Jersey, 2007, and in Richard C. Larock," Comprehensive Organic Transformations: A Guide to Functional Group Preparations ”, Second Edition, Wiley-VCH Verlag GmbH, 2000, in

60 in particular, in the relevant chapters thereof.

In an analogous manner, any of the lactams according to the present invention, or a salt thereof, wherein R1 is a nitrogen protecting group, can be converted to the corresponding lactam, or a salt thereof, into where R1 is a hydrogen, according to conventional methods of organic chemistry

65 known in the art, and in particular reference is made to the conventional nitrogen protecting group methods described in the above-mentioned books, in particular in the relevant sections.

E11734379

10-19-2015

The term "one pot" or "one pot process" means that, in a series of reactions, each reaction product is provided for the next reaction without isolation and / or purification. The term "purification", as used herein, refers in particular to crystallization, column chromatography, or distillation. The one-pot processes defined herein encompass not just a series of reactions conducted in a

5 single reaction vessel, but also a series of reactions conducted in a plurality of reaction vessels (eg, by transferring the reaction mixture from one vessel to another) without isolation and / or purification. Preferably, the one-pot process is conducted in a single reaction vessel.

The term "formaldehyde" as used herein is intended to include monomeric formaldehyde and any source of formaldehyde that is readily converted to formaldehyde. For example, "formaldehyde" as used herein includes formaldehyde in its monomeric form, as well as its various acetals, hemiacetals, and low molecular weight oligomers, such as, for example, para-formaldehyde.

The term "phase transfer catalyst", as used herein, refers to a catalytic amount of a chemical agent that increases the rate of a reaction between chemical species located in different phases (eg, immiscible liquids or solid and liquids) by drawing one of the reactants, most commonly an anion, through the interface into the other phase. These catalysts include quaternary ammonium or phosphonium salts (for example, tetra-alkyl-ammonium salts, where the alkyl may be the same or different), or agents that complex with inorganic cations (for example, ethers crown or other cryptands). The catalyst cation is not consumed in the reaction, although anion exchange does occur. In particular, suitable phase transfer catalysts for use in accordance with the present invention are quaternary ammonium salts, for example of the formula RmRnRlRkNX, where RmRnRlRk are alkyl, either the same or different, and X is halogen ( e.g. chloride, bromide, iodide) or

Hydroxide, for example tetra-n-butyl ammonium hydroxide.

The term "pro-drug", as used herein, represents in particular compounds that are transformed in vivo to the parent compound, eg, by hydrolysis in blood, eg, as described in T. Higuchi et al. V. Stella, Pro-drugs as Novel Delivery Systems, ACS Volume 14 Symposium Series, Edward

B. Roche, Editor, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; H Bundgaard, Editor, Design of Prodrugs, Elsevier, 1985; and Judkins et al., Synthetic Communications, 26 (23), 4351-4367 (1996), and "The Organic Chemistry of Drug Design and Drug Action", Second Edition, RB Silverman (in particular Chapter 8, pages 497 to 557) , Elsevier Academic Press, 2004.

35 Pro-drugs, therefore, include drugs that have a functional group that has been transformed into a reversible derivative thereof. Typically, these pro-drugs are transformed to the active drug by hydrolysis. As the examples, the following may be mentioned:

Functional group Reversible derivative Carboxylic acid Esters, including, for example, alkyl esters Alcohol Esters, including, for example, sulfates and phosphates, as well as esters of

carboxylic acids Amine Amides, carbamates, imines, enamines, Carbonyl (aldehyde, ketone) Imines, oximes, acetals / ketals, enol-esters, oxazolidines and thiazoxolidines

Pro-drugs also include compounds that can be converted to active drug by oxidative or reductive reaction. As the examples, we can mention:

Oxidative activation

45 • N- and O-dealkylation

•

Oxidative deamination

•

N-oxidation

•

Epoxidation

Reductive activation

55 • Azo reduction

•

Sulfoxide reduction

•

Disulfide reduction

E11734379

10-19-2015

•

Bio-reductive alkylation

•

Nitro reduction

Each of the reactions and / or reaction steps described above can be used individually or in combination in a method for preparing a neutral endopeptidase (NEP) inhibitor or a pro-drug thereof, such as an endopeptidase inhibitor. neutral (NEP) or a pro-drug thereof comprising a base structure of γ-amino-δ-biphenyl-α-methyl-alkanoic acid, or acid ester, such as alkyl ester. In particular the neutral endopeptidase inhibitor (NEP) is N- (3-carboxy-1-oxo-propyl) - (4S) -p-phenyl-phenyl-methyl) 4-amino- (2R) -methyl- acid. butanoic, or a salt thereof, or a pro-drug thereof. As described above, International Publication Number WO2008 / 083967 describes a process for converting a compound of formula (1), as described herein, to a neutral endopeptidase (NEP) inhibitor, or a pro-drug. of the same.

15 Section C: Examples

The following examples serve to illustrate the invention without limiting its scope, although, on the other hand, they represent the preferred embodiments of the reaction steps, intermediates, and / or the process of the present invention.

Abbreviations:

δ chemical change µl microliters Ac acetyl

25 AcOH acetic acid Bn benzyl Boc terbutoxycarbonyl BF3 -diazabicyclo- [5,4,0] -undec-7-ene

35 DME 1,2-dimethoxyethane DMPU 1,3-dimethyl-3,4,56-tetrahydro-2 (1H) -pyrimidinone of diastereomeric excess dr diastereomeric ratio DMF = dmf N, N-dimethylformamide DMSO dimethyl sulfoxide ee enantiomeric excess ES electrospray ESI electrospray ionization Et ethyl

45 EtOAc ethyl acetate EtOH ethanol h hour (s) H NMR proton nuclear magnetic resonance HCl (aq) aqueous hydrogen chloride solution HMDS 1,1,1,3,3,3-hexamethyl-disilazane HPLC liquid chromatography of high performance iPr isopropyl iPr2Net N-ethyl-dihydropropylamine iPrOAc isopropyl acetate

55 iPrOH isopropanol IR infra-red K2CO3 potassium carbonate l liters LC-MS liquid chromatography-mass spectrometry LiCl lithium chloride LDA lithium di-isopropylamide LHMDS lithium bis- (trimethylsilyl) -amide M molarity MeONa sodium methoxide

65 MgSO4 magnesium sulfate m / e ratio of mass to charge

E11734379

10-19-2015

Methyl MeOH Methanol mg milligrams min minute (s)

5 ml milliliters mmol (s) millimole (s) mol (s) mol (s) MS mass spectrometry N2 nitrogen

10 Na2CO3 sodium carbonate Na2SO3 sodium sulfite Na2SO4 sodium sulfate NH4Cl ammonium chloride nm nanometers

15 NMR nuclear magnetic resonance Ph phenyl Piv pivaloyl Piv-Cl pivaloyl chloride Ppm parts per million

20 PPTS pyridinium p-toluene sulfonate pyr pyridine TA = ta = t.a. room temperature TBAH tetra-n-butyl ammonium hydroxide tBu tertiary butyl

25 TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Tol toluene tR retention time

30 Xyl xylene

When citing nuclear magnetic resonance (NMR) data, the following abbreviations can be used: s, singlet; d, doublet; t, triplet; c, quadruplet; quint., quintuplet; m, multiplet.

35 Example 1: (S) -5-Biphenyl-4-yl-methyl-1- (4-methoxy-benzyl) -pyrrolidin-2-one (3a, R1 = p-methoxy-benzyl)

image46

H

Under N2 atmosphere, add sodium hydride (55%, 6.9 g, 158 mmol) to the mixture of (S) -5-biphenyl-4-yl-methyl

40 pyrrolidin-2-one (3a, R1 = H) (36 g, 143 mmol) in 400 ml of dry dimethylformamide at room temperature, and then 4-methoxy-benzyl chloride (24.7 g, 158 millimoles). The reaction mixture is heated to 55 ° C, and stirred for 3 hours. It is cooled to room temperature (r.t.), 5 ml of AcOH are added, and it is stirred for another 15 min; then the dimethylformamide is removed, the residue is redissolved in 400 ml of ethyl acetate, washed with water, and dried over sodium sulfate. The solvent is removed, the residue is redissolved in 100 ml

45 tert-butyl-methyl-ether, cool to 0 ° C, and stir for 5 hours, filter, and dry, to provide (S) -5-biphenyl-4-yl-methyl-1- (4-methoxy- benzyl) -pyrrolidin-2-one (3a, R1 = p-methoxy-benzyl). ¹H NMR (400 MHz, CDCl3): 1.78 (m, 1H, 3-CHH), 1.90 (m, 1H, 3-CHH), 2.28 (m, 2H, 2-CH2), 2, 59 (dd, 1H, 5-CHH), 3.05 (dd, 1H, 5-CHH), 3.80 (s, 3H, OCH3), 3.98 (d, 1H, CHH), 5.05 ( d, 1H, CHH), 6.80 ~ 7.40 (13H, m, aromatic). HPLC method

50 Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (90% B); 10 min (95% of B); 15 min (95% of B). Flow rate: 0.7 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC. Retention time: 12.5 min (3a, R1 = p-methoxy-benzyl).

E11734379

10-19-2015

Example 2: (S) -1-benzoyl-5-biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = benzoyl).

image47

image48

5 A mixture of (S) -5-biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = H) (10 g, 40 mmol), and triethylamine (16.6 ml, 120 millimoles) is heated to 60 ° C, and benzoyl chloride (8.5 g, 60 millimoles) is added over 1 hour; after an additional 4 hours, a citric acid solution (23.7 grams in 100 ml of water) is added, and the aqueous layer is washed with toluene; the organic portions are combined, washed with water, the mixture is concentrated in vacuo, and redissolved in tert-butyl-methyl-ether, and cooled in an ice-water bath, stirred for 4 hours, and filtered,

10 to provide (S) -1-benzoyl-5-biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = benzoyl). ¹H NMR (400 MHz, CDCl3): 1.94 (m, 1H, 3-CHH), 2.13 (m, 1H, 3-CHH), 2.20 (m, 1H, 2-CHH), 2, 23 (m, 1H, 2-CHH), 2.71 (d, 1H, 5-CHH), 2.96 (d, 1H, 5-CHH), 4.38 (m, 1H, 4-CH), 7.20 ~ 8.10 (14H, m, aromatic). HPLC method

15 Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (90% B); 10 min (95% of B); 15 min (95% of B). Flow rate: 0.7 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC. Retention time: 13.0 min (3a, R1 = benzoyl).

20 Example 3: (S) -5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl)

image49

OR

OR

image50

image51

Method 1

25 The (S) -5-biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = H) (10.0 g, 39.8 mmol) is dissolved in 100 ml of anhydrous tetrahydrofuran, phenyl- Acetaldehyde (5.3 g, 39.8 millimoles), and P2O5 (6.2 g, 43.8 millimoles), are added in sequence, and the reaction mixture is refluxed for 12 hours. The reaction mixture is cooled to room temperature, filtered, and the cake is washed with ethyl acetate; the filtrate is washed with an aqueous solution of

30 10% sodium bicarbonate and brine, dry over anhydrous Na2SO4 and concentrate in vacuo; The residue is recrystallized from tert-butyl-methyl-ether to obtain (S) -5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl ). ¹H NMR (400 MHz, CDCl3): 2.11 (m, 1H, 3-CHH), 2.16 (m, 2H, 5-CH2), 2.29 (m, 1H, 3CHH), 2.95 (d, 1H, 5-CH2), 3.10 (d, 1H, 5-CH2), 4.37 (m, 1H, 4-CH), 6.10 (d, 1H, C = CHH), 7.21 ~ 7.65 (15H, m, aromatic + C = CHH),

35 Method 2

The (S) -5-biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = H) (10.0 g, 39.8 mmol) is dissolved in 40 ml of anhydrous toluene, and added phenyl-acetaldehyde (5.3 g, 39.8 mmol), and TsOH * H2O (0.2 g, 1 mmol). The reaction flask is fitted with a Dean-Stark trap and condenser, and the reaction mixture is refluxed under a nitrogen atmosphere for 12 hours. The reaction mixture is cooled to room temperature, 100 ml of ethyl acetate are added, the organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate, followed by a solution of Na2SO3 and brine, the organic layer is then dried over anhydrous Na2SO4, and concentrate in vacuo; the residue is purified by flash chromatography to obtain (S) -5

E11734379

10-19-2015

Biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl). Spectroscopic data as in Example 2, Method 1.

Method 3

5 The (S) -5-biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = H) (50.2 g, 200 mmol) is dissolved in 150 ml of p-xylene, and added phenyl-acetaldehyde (26.4 g, 220 mmol), and TsOH * H2O (0.4 g, 2 mmol). The reaction flask is fitted with a Dean-Stark trap and condenser, and refluxed under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, stirred at 0 ° C for 1 hour, then filtered,

10 The cake is washed with chilled tert-butyl-methyl-ether three times (20 ml, 3 times), dried under high vacuum, to obtain (S) -5-biphenyl-4-yl-methyl-1 - (( E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl) as a white solid. Spectroscopic data as in Example 2, Method 1.

Method 4

15 The (S) -5-biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = H) (5.02 g, 20 mmol) is dissolved in 50 ml of toluene, and dimethyl- Phenyl-acetaldehyde acetal (3.77 g, 22 mmol), and TsOH * H2O (0.1 g, 0.5 mmol). The reaction flask is fitted with a Dean-Stark trap and condenser, and refluxed under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, 50 ml of acetate are added

20 of ethyl, and stirred for 10 min, to obtain a clear solution, washed with a saturated aqueous solution of sodium hydrogen carbonate, saturated aqueous Na2SO3 and brine, the organic extracts were dried over anhydrous Na2SO4, and the solvent was evaporated to the vacuum; the residue is purified by flash chromatography, to obtain (S) -5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl) as a white solid. Spectroscopic data as in Example 2, Method 1.

25 Method 5

(S) -5-Biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = H) (5.02 g, 20 mmol) is dissolved in 50 ml of toluene, and dimethyl acetal is added phenyl-acetaldehyde (3.77 g, 22 mmol), and PPTS (0.13 g, 0.5 mmol). The reaction flask is fitted with a Dean-Stark trap and condenser, and refluxed under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, 50 ml of ethyl acetate are added, and it is stirred for 10 min, to obtain a clear solution, it is washed with a saturated aqueous solution of sodium hydrogen carbonate, saturated aqueous Na2SO3 and brine. , the organic phase is dried over anhydrous NaSO4, and the solvent is evaporated in vacuo; the residue is purified by evaporative chromatography

Instant to give (S) -5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl) as a white solid. Spectroscopic data as in Example 2, Method 1. HPLC method (Methods 1-6) Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Length

40 wave: 210 nm. Temperature: 30 ºC. Retention time: 12.3 min (3a, R1 = styryl).

Example 4: (S) -5-biphenyl-4-yl-methyl-1 - ((E) -but-1-enyl) -pyrrolidin-2-one (3a, R1 = 1-butenyl)

Image52

image53

OR

OR

image54

Four. Five

Method 1

50 La (S) -5-biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = H) (10.0 g, 39.8 mmol) is dissolved in 100 ml of anhydrous tetrahydrofuran, added butyl aldehyde (2.9 g, 39.8 mmol), and phosphorous pentoxide (6.2 g, 43.2 mmol) in sequence, the reaction mixture is refluxed for 12 hours. The reaction mixture is cooled to room temperature, filtered, and washed with ethyl acetate, the filtrate is washed with an aqueous solution of

E11734379

10-19-2015

10% sodium hydrogen carbonate, followed by brine. The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo; the residue is purified by flash column chromatography in heptane / ethyl acetate = 10: 1, to give (S) -5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidine -2-one (3a, R1 = 1-butenyl). ¹H NMR (400 MHz, CDCl3): 1.07 (t, 3H, CH3H), 2.12 (m, 2H, CH2H), 2.20 (m, 2H, 3-CH2), 2.35 (m , 2H, 2

5CH2), 2.95 (m, 1H, 5-CH2), 3.13 (m, 1H, 5-CH2), 4.14 (m, 1H, 4-CH), 5.27 (m, 1H , CH = CH), 6.85 (d, 1H, HC = CH-N), 7.14 ~ 7.51 (9H, m, aromatic).

Method 2

10 The (S) -5-biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = H) (5.02 g, 20 mmol) is dissolved in 50 ml of toluene, butyl-aldehyde is added (1.44 g, 20 mmol), and TsOH * H2O (50 mg, 0.3 mmol). The reaction flask is fitted with a Dean-Stark trap and condenser, and refluxed under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, 50 ml of toluene are added, it is stirred for 10 min to obtain a clear solution, it is washed with a saturated aqueous solution of sodium hydrogen carbonate,

15 saturated aqueous Na2SO3 and brine, the organic phase is dried over anhydrous Na2SO4, and the solvent is evaporated in vacuo; The residue is purified by flash chromatography to obtain (S) -5-biphenyl-4-ylmethyl-1 - ((E) -but-1-enyl) -pyrrolidin-2-one (3a, R1 = 1 -butenyl). Spectroscopic data as in Example 4, Method

1.

20 Method 3

(S) -5-Biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = H) (5.02 g, 20 mmol) is dissolved in 50 ml of toluene, butyl-aldehyde ( 1.44 g, 20 mmol), and BF3-Et2O (0.5 ml). The reaction flask is fitted with a Dean-Stark trap and condenser, and refluxed under a nitrogen atmosphere overnight. The

The reaction mixture is cooled to room temperature, 50 ml of toluene are added, stirred for 10 min, to obtain a clear solution, washed with a saturated aqueous solution of sodium hydrogen carbonate, saturated aqueous Na2SO3 and brine, the phase Organic is dried over anhydrous Na2SO4, and the solvent is evaporated in vacuo; The residue is purified by flash chromatography to obtain (S) -5-biphenyl-4-yl-methyl-1 - ((E) but-1-enyl) -pyrrolidin-2-one (3a, R1 = 1-butenyl). Spectroscopic data as in Example 4, Method 1.

30 Method 4

(S) -5-Biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = H) (5.0 g, 20 mmol) is dissolved in 50 ml of tetrahydrofuran, diethyl acetal of butyl aldehyde (3.2 g, 22 mmol), and PPTS (215 mg, 1 mmol). The reaction flask

35 is fitted with distillation equipment and a condenser to remove the ethanol produced in the reaction, and refluxed under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, 50 ml of toluene are added, it is washed with a saturated aqueous solution of sodium hydrogen carbonate, saturated aqueous Na2SO3 and brine, the organic phase is dried over anhydrous Na2SO4, and the solvent is evaporated to the vacuum; The residue is purified by flash chromatography to obtain (S) -5-biphenyl-4-yl-methyl-1 - ((E)

But-1-enyl) -pyrrolidin-2-one (3a, R1 = 1-butenyl). Spectroscopic data as in Example 4, Method 1.

Method 5

(S) -5-Biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = H) (5.0 g, 20 mmol) is dissolved in 50 ml of toluene,

45 add butyl aldehyde diethyl acetal (3.2 g, 22 mmol), and PPTS (215 mg, 1 mmol). The reaction flask is fitted with distillation equipment and a condenser to remove the ethanol produced in the reaction, and heated to reflux under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, 50 ml of toluene are added, it is washed with a saturated aqueous solution of sodium hydrogen carbonate, saturated aqueous Na2SO3 and brine, the organic phase is dried over anhydrous Na2SO4, and the solvent is evaporated to the

50 empty; The residue is purified by flash chromatography to give (S) -5-biphenyl-4-yl-methyl-1 - ((E) -but-1-enyl) -pyrrolidin-2-one (3a, R1 = 1 -butenyl). Spectroscopic data as in Example 4, Method 1. HPLC method (Methods 1-5) Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Length

55 wave: 210 nm. Temperature: 30 ºC. Retention time: 9.5 min (3a, R1 = 1-butenyl).

E11734379

10-19-2015

Example 5: (3R / S) -benzoyl- (5S) -biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4a, R1 = t-butoxycarbonyl, R4 = phenyl)

image55

5 Method 1

Under N2 atmosphere, n-butyllithium (56 ml, 2.5 M in hexane, 0.14 mol) is added to the mixture of HMDS (24.2 g, 0.15 mol) in 300 ml dry tetrahydrofuran at -10 ° C, and the resulting mixture is then stirred for 30 min at -10 ° C. 10 A mixture of (S) -2-biphenyl-4-yl-methyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3a, R1 = t-butoxycarbonyl) (35.1 g, 0.1 moles) in 50 ml of dry tetrahydrofuran, is added to the reaction mixture at -10 ° C; after about 30 min, n-butyllithium (40 ml, 2.5 M in hexane, 0.1 mol) is added to the reaction mixture at -10 ° C, and the resulting mixture is then stirred for 30 min at -10 ° C. Benzoyl chloride (15.5 g, 0.11 mol) is added to the reaction mixture at -10 ° C; after about 1 hour at -10 ° C, the reaction mixture is diluted with 100 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed; the organic phase is then concentrated in vacuo. Ethyl acetate (200 ml) is added, filtered, and the filtrate is concentrated to give the acid tert-butyl ester (R / S) -3-benzoyl (S) -5-biphenyl-4-yl-methyl-2 -oxo-pyrrolidine-1-carboxylic (4a, R1 = t-butoxycarbonyl, R4 = phenyl); the ratio of (3S, 5R) :( 3R, 5R) is 70:30, as determined by HPLC. ¹H NMR (400 MHz, DMSO): 1.52 (s, 9H, (CH3) 3),

2.05 (m, 1H, 3-CHH), 2.60 (m, 1H, 3CHH), 2.96 (m, 1H, 5-CHH), 3.13 (m, 1H, 5-CHH) , 4.21 (m, 1H, 2-CH), 4.53 (m, 1H, 4-CH), 7.10 ~ 8.10 (14H, m, aromatic).

Method 2

Under N2 atmosphere, add n-butyllithium (2.4 ml, 2.5 M in hexane, 6 millimoles) to the di-isopropylamine mixture (0.71 g, 7 millimoles) in 20 ml of dry tetrahydrofuran at -10 ° C, and the resulting mixture is then stirred for 30 min at -10 ° C. A mixture of (S) -2-biphenyl-4-yl-methyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3a, R1 = t-butoxycarbonyl) (1.76 g, 5 mmol) in 5 ml of dry tetrahydrofuran, to the reaction mixture at -10 ° C; after about 30 min, n-butyllithium (2 mL, 2.5 M in hexane, 5 mmol) is added to the mixture of

30 reaction at -10 ° C, and the resulting mixture is then stirred for 30 min at -10 ° C. Benzoyl chloride (0.77 g, 5.5 mmol) is added to the reaction mixture at -10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 100 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the filtrate is concentrated to give (R / S) -3-benzoyl acid tert-butyl ester.

(S) -5-Biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic (4a, R1 = t-butoxycarbonyl, R4 = phenyl). The ratio of (3S, 5R) :( 3R, 5R) is 70:30, as determined by HPLC. Spectroscopic data as in Example 5, Method 1.

Method 3

40 Under N2 atmosphere, LHMDS (132 ml, 1.0 M in tetrahydrofuran, 132 mmol) is added to the (S) -2-biphenyl-4-yl-methyl-5-oxo-pyrrolidine-acid tert-butyl ester mixture. 1-carboxylic (3a, R1 = t-butoxycarbonyl) (21.06 g, 60 mmol) in 150 ml of dry tetrahydrofuran to the reaction mixture at -10 ° C, and the resulting mixture is then stirred for 30 min at -10 ° C. Benzoyl chloride (9.28 g, 66 mmol) is added to the reaction mixture at

45 10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 50 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (100 ml) is added, filtered, and the filtrate is concentrated to give (R / S) -3-benzoyl- (S) -5-biphenyl-4-yl-methyl-acid tert-butyl ester. 2-oxo-pyrrolidine-1-carboxylic acid (4a, R1 = t-butoxycarbonyl, R4 = phenyl). The ratio of (3S, 5R) :( 3R, 5R) is 70: 30, as shown

50 determined by HPLC. Spectroscopic data as in Example 5, Method 1.

E11734379

10-19-2015

Method 4

Under N2 atmosphere, (S) -2-biphenyl-4-yl-methyl-5-oxo-pyrrolidine-1-carboxylic acid (3a, R1 = t-butoxycarbonyl) (1.4 g, 4 millimoles) is dissolved in 4 ml of toluene, and heated under reflux; add sodium hydride (55% in mineral oil, 0.23 g, 5.2 mmol), and stir for 2 hours under reflux; Benzoyl chloride (0.62 g, 4.4 mmol) is then added to the reaction mixture, and the resulting mixture is then stirred for 2 hours under reflux. The reaction mixture is diluted with 5 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is concentrated to dryness, the residue is purified by column chromatography (ethyl acetate / heptane = 1/2), to give the

10 (R / S) -3-Benzoyl- (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4a, R1 = t-butoxycarbonyl, R4 = phenyl). The ratio of (3S, 5R) :( 3R, 5R) is 70:30, as determined by HPLC. Spectroscopic data as in Example 5, Method 1.

Method 5

15 Under N2 atmosphere, to a solution of (S) -2-biphenyl-4-yl-methyl-5-oxo-pyrrolidine-1-carboxylic acid (3a, R1 = t-butoxycarbonyl) ( 10 g, 28.49 mmol) in tetrahydrofuran (56 ml), MgCl2 (2.56 g, 28.49 mmol), and triethylamine (8.63 g, 85.47 mmol) are added. The mixture is cooled to 5 ° C, stirred for 10 min, and then benzoyl chloride (6.40 g, 45.58 mmol) is added dropwise. The reaction mixture is stirred at 5 ° C for 1

20 hours, then the temperature warms up to 10 ° C. After stirring for 15 hours, 20 ml of water are added, followed by a solution of H3PO4 (12.0 grams) in water (20 ml). The aqueous phase is then removed, the organic phase is washed with brine (40 ml) twice, and the organic extracts are concentrated in vacuo, to give the acid tert-butyl ester (R / S) -3-benzoyl- (S ) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid (4a, R1 = tert-butoxycarbonyl, R4 = phenyl). The ratio of (3S, 5R) :( 3R, 5R) is 70:30, as determined by HPLC. Data

25 spectroscopic as in Example 5, Method 1. HPLC method (Methods 1-5) Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC.

30 Retention time:

10.3 min (3S, 5R-4, R1 = tert-butoxycarbonyl, R4 = phenyl). 10.5 min (3R, 5R-4, R1 = tert-butoxycarbonyl, R4 = phenyl). 9.2 min (3a, R1 = t-butoxycarbonyl).

35 Example 6: (R / S) -3-benzoyl- (S) -5-biphenyl-4-yl-methyl-1-pyrrolidin-1-yl-methyl-pyrrolidin-2-one (4a, R1 = pyrrolidinyl- methyl, R4 = phenyl).

image56

Image57

40 Method 1

Under N2 atmosphere, the mixture of (S) -5-biphenyl-4-yl-methyl-1-pyrrolidin-1-yl-methyl-pyrrolidin-2-one (3a, R1 = pyrrolidinylmethyl) (6.68 g , 20 millimoles), and benzoic acid methyl ester (3.0 g, 22 millimoles) in 20 ml of toluene, heated under reflux; add sodium hydride (55% in mineral oil, 1.14 g, 26 mmol), and stir overnight under reflux. The reaction mixture is diluted with 20 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is concentrated to dryness, the residue is purified by column chromatography (ethyl acetate / heptane = 1/1), to give (R / S) -3-benzoyl- (R) -5-biphenyl-4 -yl-methyl-1-pyrrolidin-1-yl-methyl-pyrrolidin-2-one (4a, R1 = pyrrolidinyl-methyl, R4 = phenyl); the

The ratio of (3S, 5R) and (3R, 5R) is 60:40, as determined by HPLC. ¹H NMR (400 MHz, CDCl3): 1.68 (m, 4H, 2xCH2CH2), 1.98 (m, 1H, 3-CHH), 2.23 (m, 1H, 3-CHH), 2.51 ( m, 4H, 2xNCH2), 2.65 (dd, 1H, N-CHH), 3.15 (dd, 1H, N-CHH), 2.67 (d, 1H, 5-CHH), 2.92 ( d, 1H, 5-CHH), 3.73 (m, 1H, 2-CH), 3.78 (m, 1H, 4-CH), 7.20-8.00 (14H, m, aromatic).

E11734379

10-19-2015

Method 2

Under N2 atmosphere, the mixture of (S) -5-biphenyl-4-yl-methyl-1-pyrrolidin-1-yl-methyl-pyrrolidin-2-one (3a, R1 = pyrrolidinylmethyl) (1.34 g , 4 mmol), and benzoic acid methyl ester (0.6 g, 4.4 mmol) in 4 ml of dimethylformamide is stirred at 20 ° C; add sodium hydride (55% in mineral oil, 0.23 g, 5.2 mmol), and stir overnight at 110 ° C. The reaction mixture is diluted with 5 ml of a saturated aqueous ammonium chloride solution and 10 ml of ethyl acetate, stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is concentrated to dryness, the residue is purified by column chromatography (ethyl acetate / heptane = 1/1), to give (R / S) -3-benzoyl- (R) -5-biphenyl-4 -yl-methyl-1-pyrrolidin-1-yl-methyl-pyrrolidin-2-one (4a, R1 =

10 pyrrolidinyl-methyl, R4 = phenyl); the ratio of (3S, 5R), and (3R, 5R) is 60:40, as determined by HPLC. Spectroscopic data as in Example 6, Method 1.

Method 3

15 In an N2 atmosphere, the mixture of (S) -5-biphenyl-4-yl-methyl-1-pyrrolidin-1-yl-methyl-pyrrolidin-2-one (3a, R1 = pyrrolidinylmethyl) (1.34 g, 4 mmol), DMPU (0.56 g, 4.4 mmol), and benzoic acid methyl ester (0.6 g, 4.4 mmol) in 4 ml of dimethylformamide is stirred at 20 ° C; Sodium hydride (55% in mineral oil, 0.23 g, 5.2 mmol) is added, and it is stirred for 3 hours at 110 ° C. The reaction mixture is diluted with 5 ml of a saturated aqueous ammonium chloride solution and 10 ml of ethyl acetate, stirred for 15 min, stirring is discontinued, and

20 removes the lower aqueous layer. The organic phase is concentrated to dryness, and the residue is purified by column chromatography (ethyl acetate / heptane = 1/1), to give (R / S) -3-benzoyl- (R) -5-biphenyl- 4-yl-methyl-1-pyrrolidin-1-yl-methyl-pyrrolidin-2-one (4a, R1 = pyrrolidinyl-methyl, R4 = phenyl); the ratio of (3S, 5R), and (3R, 5R) is

60:40, as determined by HPLC. Spectroscopic data as in Example 6, Method 1.

25 Method 4

Under N2 atmosphere, the mixture of (S) -5-biphenyl-4-yl-methyl-1-pyrrolidin-1-yl-methyl-pyrrolidin-2-one (3a, R1 = pyrrolidinylmethyl) (1.34 g , 4 mmol), DMPU (0.56 g, 4.4 mmol), and benzoic acid methyl ester (0.6 g, 4.4 mmol) in 4 ml of toluene is stirred at 20 ° C; add sodium hydride (55% in mineral oil, 0.23 g, 5.2 mmol), and

30 stir for 3 hours at 60 ° C. The reaction mixture is diluted with 5 ml of a saturated aqueous ammonium chloride solution and 10 ml of ethyl acetate, stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is concentrated to dryness, the residue is purified by column chromatography (ethyl acetate / heptane = 1/1), to give (R / S) -3-benzoyl- (R) -5-biphenyl-4 -yl-methyl-1-pyrrolidin-1-yl-methyl-pyrrolidin-2one (4a, R1 = pyrrolidinyl-methyl, R4 = phenyl); the ratio of (3S, 5R) and (3R, 5R) is 60:40, as determined

35 by HPLC. Spectroscopic data as in Example 6, Method 1. HPLC method (Methods 1-4) Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (90% B); 10 min (95% of B); 15 min (95% of B). Flow rate: 0.7 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC.

40 Retention time:

8.6 min (3S, 5R-4, R1 = pyrrolidinyl-methyl, R4 = phenyl). 8.8 min (3R, 5R-4, R1 = pyrrolidinyl-methyl, R4 = phenyl). 7.5 min (3a, R1 = pyrrolidinyl-methyl).

45 Example 7: (3R / S) -benzoyl- (5S) -biphenyl-4-yl-methyl-1- (4-methoxy-benzyl) -pyrrolidin-2-one (4a, R1 = p-methoxy-benzyl, R4 = phenyl).

Image58

image59

image60

OMe

To a suspension of sodium hydride (150 mg, 55% in mineral oil, 3.75 mmol) in toluene (1 milliliter), (5S) -biphenyl-4-yl-methyl-1- (4- methoxy-benzyl) -pyrrolidin-2-one (3a, R1 = p-methoxy-benzyl) (694 mg, 1.86 mmol), followed by the addition of benzoic acid methyl ester (253 mg, 1.86 mmol ), the resulting mixture

E11734379

10-19-2015

then it is heated at 130 ° C for 9 hours. After cooling to room temperature, NH4Cl (saturated aqueous, 5 ml) is added, followed by ethyl acetate (3 ml). The organic layer is separated, washed with brine, and concentrated to give (3R / S) -benzoyl- (5S) -biphenyl-4-yl-methyl-1- (4-methoxy-benzyl) -pyrrolidin-2 -one (4a, R1 = p-methoxybenzyl, R4 = phenyl) as a mixture of diastereomers (3S, 5R) and (3R, 5R) (50:40, as determined by

5 HPLC). ¹H NMR (400 MHz, DMSO): 1.82-2.08 (m, 2H), 2.25-2.70 (m, 2H), 3.00-3.26 (m, 2H), 3, 73 (s, 3H), 4.00-4.10 (m, 1H), 4.20-4.52 (m, 1H), 4.94-5.09 (m, 1H), 6.86 ~ 8.10 (18H, m, aromatic). MS (ESI, m / e) 476 (MH +). Column HPLC method: Eclipse XDB-C18; 150 × 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Length

10 wave: 210 nm. Temperature: 30 ºC. Holding time:

10.0 min (3S, 5S-4, R1 = p-methoxy-benzyl, R4 = phenyl). 10.1 min (3R, 5S-4a, R1 = p-methoxy-benzyl, R4 = phenyl). 8.8 min (3a, R1 = p-methoxy-benzyl).

Example 8: (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = benzyl).

image61

image62

image63

20 Method 1

The (S) -5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl) (50.0 g, 141.7 mmol) is heated To dissolve in 140 ml of anhydrous toluene under N2 atmosphere, add sodium hydride (8.04 g, 184.2 mmol) in

25 portions, stir at this temperature for 10 min, then add methyl benzoate dropwise, reflux for 6 hours, cool to room temperature, quench with a saturated aqueous solution of NH4Cl, separate the organic phase , extracted with toluene (100 ml, 3 times), the combined organic extracts are washed with a saturated aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo to obtain (S) -3- benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl); the

The ratio of (3S, 5S) to (3R, 5S) is 70:30, as determined by HPLC. ¹H NMR (400 MHz, CDCl3): 2.35 (m, 1H, 3-CHH), 3.26 (m, 3H, 5-CH2 + 3-CHH), 3.74 (m, 1H, 2- CH), 4.32 (m, 1H, 4-CH), 6.21 (m, 1H, C = CHH), 7.21 ~ 7.80 (m, 20H, aromatic + C = CHH).

Method 2

35 (S) -5-Biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl) (10.0 g, 28.3 mmol) is heat to dissolve in 30 ml of anhydrous toluene under N2 atmosphere, add MeONa (1.99 g, 36.8 mmol) in one portion, stir at this temperature for 10 min, then add methyl benzoate dropwise, reflux overnight, cool to room temperature, quench with a saturated aqueous NH4Cl solution,

The organic phase is separated, extracted with toluene (15 ml, 3 times), the combined organic extracts are washed with a saturated aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with 5: 1 heptane / ethyl acetate, to give (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - (( E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl); the ratio of (3S, 5S) to (3R, 5S) is 70:30, as determined by HPLC. Spectroscopic data such as

45 in Example 8, Method 1.

Method 3

The (S) -5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl) (1.00 g, 2.8 mmol) is heated for

50 dissolved in 3 ml of anhydrous toluene under N2 atmosphere, add t-BuOK (0.43 g, 3.7 mmol) in one portion, stir at this temperature for 10 min, then add methyl benzoate dropwise , the reaction mixture is refluxed overnight, cooled to room temperature, quenched with a saturated aqueous solution of NH4Cl, the organic phase is separated, extracted with toluene (30 ml, 3 times), the organic extracts combined they

E11734379

10-19-2015

Washed with a saturated aqueous Na2CO3 solution and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with 5: 1 heptane / ethyl acetate, to obtain (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - (( E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl); the ratio of (3S, 5S) to (3R, 5S) is 70:30, as determined by HPLC. Data

5 spectroscopic as in Example 8, Method 1. HPLC method (Methods 1-3) Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC.

10 Retention time:

10.7 min (3S, 5S-4, R1 = styryl, R4 = phenyl). 11.0 min (3R, 5S-4, R1 = styryl, R4 = phenyl). 12.3 min (3a, R1 = styryl)

15 Example 9: (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -but-1-enyl) -pyrrolidin-2-one (4a, R1 = 1-butenyl, R4 = phenyl).

image64

image65

image66

20 Sodium hydride (2.03 g, 46.4 mmol) is suspended in 40 ml of anhydrous toluene, heated to reflux under a nitrogen atmosphere, a solution of (S) -5-biphenyl is added to the mixture -4-yl-methyl-1 - ((E) -but-1-enyl) -pyrrolidin2-one (3a, R1 = 1-butenyl) (11.02 g, 35.67 mmol), and methyl benzoate ( 4.86 g, 35.67 mmol) in anhydrous toluene dropwise, the reaction mixture is refluxed for 4 hours, cooled to room temperature, quenched with a saturated aqueous solution of NH4Cl, extracted with toluene, the combined organic extracts are

Wash with saturated Na2CO3 and brine, dry over anhydrous Na2SO4, and concentrate in vacuo, to obtain (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -but- 1-enyl) -pyrrolidin-2-one (4a, R1 = 1-butenyl, R4 = benzyl), which is used directly in the next step. ¹H NMR (400 MHz, CDCl3): 1.07 (t, 3H, CH3H), 2.12 (m, 2H, CH2H), 2.20 (m, 2H, 3-CH2), 2.95 (m , 1H, 5-CH2), 3.13 (m, 1H, 5-CH2), 3.82 (m, H, 2-CH2H), 4.14 (m, 1H, 4-CH), 5.27 (m, 1H, CH = CH), 6.85 (d, 1H, HC = CH-N), 7.14 ~ 8.20 (14H, m, aromatic). The ratio of (3S, 5S) to (3R, 5S) is 60:40, as shown

30 determined by HPLC. Column HPLC method: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC.

35 Retention time:

10.5 min (3S, 5S-4, R1 = 1-butenyl, R4 = phenyl). 10.8 min (3R, 5S-4, R1 = 1-butenyl, R4 = phenyl). 9.5 min (3a, R1 = 1-butenyl).

40

E11734379

10-19-2015

Example 10: (R / S) -1,3-dibenzoyl- (S) -5-biphenyl-4-yl-methyl-pyrrolidin-2-one (4a, R1 = benzoyl, R4 = phenyl).

image67

Image68

image69

5 Under N2 atmosphere, 1-benzoyl- (S) -5-biphenyl-4-yl-methyl-pyrrolidin-2-one (3a, R1 = benzoyl) (1.34 g, 4 mmol) dissolves in 4 ml of toluene, and heated under reflux; add sodium hydride (55% in mineral oil, 0.23 g, 5.2 mmol), and stir for 2 hours at reflux, then add benzoyl chloride (0.62 g, 4.4 mmol) to the reaction mixture, and the resulting mixture is then stirred for 2 hours under reflux. The reaction mixture is diluted with 5 ml of a saturated aqueous solution of ammonium chloride, and stirred for 15 min, the mixture is interrupted.

10 stirring, and the lower aqueous layer is removed. The organic phase is concentrated to dryness, and the residue is purified by column chromatography (ethyl acetate / heptane = 1/2), to provide (R / S) -1,3-dibenzoyl- (S) -5-biphenyl- 4-yl-methyl-pyrrolidin-2-one (4a, R1 = benzoyl, R4 = phenyl); the ratio of (3S, 5S) to (3R, 5S) is 30:70, as determined by HPLC. ¹H NMR (400 MHz, CDCl3): 2.09 (m, 1H, 3-CHH), 2.34 (m, 1H, 3-CHH), 2.71 (d, 1H, 5-CHH), 2, 96 (d, 1H, 5-CHH), 3.73 (m, 1H, 2-CH), 4.38 (m, 1H, 4-CH), 7.20 ~ 8.10 (19H, m, aromatic ).

15 HPLC method Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC. Holding time:

11.0 min (3S, 5S-4, R1 = benzoyl, R4 = phenyl). 11.1 min (3R, 5S-4, R1 = benzoyl, R4 = phenyl). 9.3 min (3a, R1 = benzoyl).

25 Example 11: (R / S) -3-Acetyl- (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester `(4a, R1 = tbutoxy- carbonyl, R4 = methyl).

image70

image71

30 Under N2 atmosphere, add LHMDS (12.5 ml, 1.0 M in tetrahydrofuran, 12.5 mmol) to the mixture of the (S) -2-biphenyl-4-yl-methyl-5- oxo-pyrrolidine-1-carboxylic (3a, R1 = t-butoxy-carbonyl) (1.76 g, 5 mmol) in 15 ml of dry tetrahydrofuran, and added to the reaction mixture at -10 ° C, and the mixture The resulting mixture is then stirred for 30 min at -10 ° C. Acetyl chloride (0.47 g, 6 mmol) is added to the reaction mixture at 10 ° C; after about 1 hour at -10 ° C, the reaction mixture is diluted with 10 ml of a solution

35 saturated aqueous ammonium chloride, and stir for 15 min, stop stirring, and remove the lower aqueous layer. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the filtrate is concentrated to give (R / S) -3-acetyl- (S) -5-biphenyl-4-yl-methyl tert-butyl ester. -2-oxo-pyrrolidine-1-carboxylic acid (3a, R1 = t-butoxycarbonyl); the ratio of (3S, 5S) to (3R, 5S) is 70:30, as determined by HPLC. ¹H NMR (400 MHz, CDCl3): 1.48 (s, 9H, (CH3) 3), 2.17 (m, 1H, 3-CHH), 2.31 (s, 3H, CH3), 2.42 (m, 1H,

3CHH), 2.67 (m, 1H, 5-CHH), 2.92 (m, 1H, 5-CHH), 3.09 (m, 1H, 2-CH), 4.38 (m, 1H , 4-CH), 7.10 ~ 7.80 (9H, m, aromatic).

E11734379

10-19-2015

Column HPLC method: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC.

5 Retention time:

9.3 min (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = methyl) 9.5 min (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = methyl). 9.2 min (3a, R1 = t-butoxycarbonyl).

10 Example 12: (R / S) -3-isobutyryl- (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4a, R1 = tbutoxycarbonyl , R4 = isopropyl).

image72

15 Under N2 atmosphere, add LHMDS (12.5 ml, 1.0 M in tetrahydrofuran, 12.5 mmol) to the (S) -2-biphenyl-4-yl-methyl-5- oxo-pyrrolidine-1-carboxylic (3a, R1 = t-butoxy-carbonyl) (1.76 g, 5 mmol) in 15 ml of dry tetrahydrofuran, and added to the reaction mixture at -10 ° C, and the mixture The resulting mixture is then stirred for 30 min at -10 ° C. Isobutyryl chloride (0.64 g, 6 mmol) is added to the reaction mixture at

20 10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 10 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the filtrate is concentrated to give (R / S) -3-isobutyryl- (S) -5-biphenyl-4-yl-methyl tert-butyl ester. -2-oxo-pyrrolidine-1-carboxylic acid (4a, R1 = t-butoxycarbonyl, R4 = isopropyl); the ratio of (3S, 5S) to (3R, 5S) is 70:30, as shown

25 determined by HPLC. ¹H NMR (400 MHz, CDCl3): 1.03 (d, 3H, CH3), 1.05 (d, 3H, CH3), 1.43 (s, 9H, (CH3) 3), 2.18 (m , 1H, 3-CHH), 2.43 (m, 1H, 3CHH), 2.70 (m, 1H, CH), 2.67 (m, 1H, 5-CHH), 2.92 (m, 1H , 5-CHH), 3.09 (m, 1H, 2-CH), 4.38 (m, 1H, 4-CH), 7.10 ~ 7.80 (9H, m, aromatic). Column HPLC method: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B

30 (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC. Holding time:

10.2 min (3S, 5S-4, R1 = tert-butoxycarbonyl, R4 = isopropyl). 10.5 min (3R, 5S-4, R1 = tert-butoxycarbonyl, R4 = isopropyl). 9.2 min (3a, R1 = t-butoxycarbonyl).

Example 13: (R / S) -3- (2,2-Dimethyl-propionyl) - (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester ( 4a, R1 = t-butoxycarbonyl, R4 = t-butyl) 40

image73

E11734379

10-19-2015

Under N2 atmosphere, add LHMDS (12.5 ml, 1.0 M in tetrahydrofuran, 12.5 mmol) to the (S) -2-biphenyl-4-yl-methyl-5-oxo acid tert-butyl ester mixture. -pyrrolidine-1-carboxylic (3a, R1 = t-butoxy-carbonyl) (1.76 g, 5 mmol) in 15 ml of dry tetrahydrofuran, and added to the reaction mixture at -10 ° C, and the resulting mixture then stir for 30 min at -10 ° C. 2,2-Dimethyl-propionyl chloride (0.72 g, 6 milli-moles) is added to the reaction mixture at -10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 10 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the filtrate is concentrated to give the acid tert-butyl ester (R / S) -3- (2,2-dimethyl-propionyl) - (S) -5 -biphenyl-4-yl-methyl-2-oxopyrrolidine-1-carboxylic acid (4a, R1 = t-butoxycarbonyl, R4 = isopropyl); the ratio of (3S, 5S) to (3R, 5S) is 80:

10-20, as determined by HPLC. ¹H NMR (400 MHz, CDCl3): 0.98 (s, 9H, 3CH3), 1.52 (s, 9H, (CH3) 3), 2.19 (m, 1H, 3-CHH), 2.42 (m, 1H, 3CHH), 2.67 (m, 1H, 5-CHH), 2.92 (m, 1H, 5-CHH), 3.09 (m, 1H, 2-CH), 4.38 (m, 1H, 4-CH), 7.10 ~ 7.80 (9H, m, aromatic). Column HPLC method: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B

15 (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC. Holding time:

10.3 min (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = isopropyl). 10.5 min (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = isopropyl). 9.2 min (3a, R1 = t-butoxycarbonyl).

Example 14: (S) -5-Biphenyl-4-yl-methyl-3-isobutyryl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = isopropyl).

OR image74

OR image75 image76 NO

25

Method 1

The (S) -5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl) (5.0 g, 14.2 mmol) is heated for

30 dissolved in 15 ml of anhydrous toluene, then sodium hydride (0.8 g, 18.4 mmol) is added in portions, stirred under a nitrogen atmosphere for 30 min, then methyl isobutyrate (1 , 7 g, 15.6 mmol, 98% purity), the reaction mixture is refluxed under nitrogen overnight, cooled to room temperature, quenched with saturated NH4Cl, extracted with toluene, the combined extracts are washed with saturated Na2CO3 and brine, dried over anhydrous Na2SO4, the solvent is evaporated in vacuo; and the residue is

35 purify by column chromatography to obtain (S) -5-biphenyl-4-yl-methyl-3-isobutyryl-1 - ((E) -styryl) -pyrrolidin2-one (4a, R1 = styryl, R4 = isopropyl ). ¹H NMR (400 MHz, CDCl3): 1.02 (m, 6H, C (CH3) 2), 2.05 (m, 1H, 3-CHH), 2.46 (m, 1H, 3-CHH), 2.97 (m, 1H, 5-CH2H), 3.10 (m, 1H, CH (CH3) 2)), 3.17 (m, 1H, 5-CH2H), 3.22 (m, 1H, 2-CHH), 4.46 (m, 1H, 4-CH), 6.10 (d, 1H, C = CHH), 7.21 ~ 7.65 (15H, m, aromatic + C = CHH) . The ratio of (3S, 5S) to (3R, 5S) is 70:30, as determined by HPLC.

40 Method 2

(S) -5-Biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl) (2.0 g, 5.7 mmol) dissolves in 15 ml of anhydrous tetrahydrofuran, cool to -10 ° C to about -15 ° C by means of an ice / salt bath, add LiHMDS (14.2 ml, 14.2 mmol, 1 M in tetrahydrofuran) dropwise a nitrogen atmosphere; The resulting mixture is stirred at this temperature for 30 min, then a solution of isobutyryl chloride (820 mg, 6.8 mmol) in 5 ml of anhydrous tetrahydrofuran is added dropwise, the temperature is kept below -5 ° C, stir for 1 hour, quench with a saturated aqueous solution of NH4Cl, add 50 ml of ethyl acetate, separate the aqueous phase, wash with a saturated aqueous solution of Na2CO3 and brine,

50 dry over anhydrous Na2SO4, and evaporate the solvent in vacuo, to obtain (S) -5-biphenyl-4-yl-methyl-3-isobutyryl-1 ((E) -styryl) -pyrrolidin-2-one ( 4a, R1 = styryl, R4 = isopropyl), which is used directly in the next step. The ratio of (3S, 5S) to (3R, 5S) is 70:30, as determined by HPLC. Spectroscopic data as in Example 14, Method 1.

E11734379

10-19-2015

HPLC method (Methods 1 and 2) Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC.

5 Retention time:

10.7 min (3S, 5S-4, R1 = styryl, R4 = isopropyl). 11.1 min (3R, 5S-4, R1 = styryl, R4 = isopropyl). 9.5 min (3a, R1 = styryl).

10 Example 15: (S) -5-Biphenyl-4-yl-methyl-3- (2,2-dimethyl-propionyl) -1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = tbutyl).

image77

image78

image79

15 Method 1

The (S) -5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl) (5.0 g, 14.2 mmol) is heated to dissolve in 15 ml of anhydrous toluene, then sodium hydride (0.8 g, 18.4 mmol) is added in portions, stirred under a nitrogen atmosphere for 30 min, then sodium trimethyl acetate chloride is added. methyl (1.9 g, 15.6 mmol) dropwise, the reaction mixture is refluxed under nitrogen overnight, cooled to room temperature, quenched with saturated NH4Cl, extracted with toluene, the combined extracts washed with saturated Na2CO3 and brine, dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo; the residue is purified by column chromatography to obtain (S) -5-biphenyl-4-yl-methyl-3- (2,2-dimethyl-propionyl) -1 - ((E)

25 styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = t-butyl). H NMR (400 MHz, CDCl3): 1.02 (s, 9H, C (CH3)), 2.05 (m, 1H, 3-CHH), 2.46 (m, 1H, 3-CHH), 2 , 97 (m, 1H, 5-CH2H), 3.17 (m, 1H, 5-CH2H), 3.22 (m, 1H, 2-CHH), 4.46 (m, 1H, 4-CH) , 6.15 (d, 1H, C = CHH), 7.21 ~ 7.65 (15H, m, aromatic + C = CHH). The ratio of (3S, 5S) to (3R, 5S) is 82:18, as determined by HPLC.

30 Method 2

(S) -5-Biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (3a, R1 = styryl) (2.0 g, 5.7 mmol) dissolves in 15 ml of anhydrous tetrahydrofuran, cool to -10 to about -15 ° C using an ice / salt bath, add LiHMDS (14.2 ml, 14.2 mmol, 1 M in tetrahydrofuran) dropwise under an atmosphere of nitrogen, the resulting mixture is stirred at this temperature for 30 min, then isobutyryl chloride (820 mg, 6.8 mmol) is added dropwise as a solution in 5 ml of anhydrous tetrahydrofuran, the temperature is kept below - 5 ° C, stir for 1 hour, quench with a saturated aqueous solution of NH4Cl, add 50 ml of ethyl acetate, separate the aqueous phase, wash with a saturated aqueous solution of Na2CO3 and brine, and dry over Na2SO4 anhydrous, and the solvent is evaporated in vacuo, to obtain (S) -5-biphenyl-4-yl-methyl-3- (2,2-dimethyl-propionyl) -1 - ((E)

40 styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = t-butyl), which is used directly in the next step. The ratio of (3S, 5S) to (3R, 5S) is 80:20, as determined by HPLC. Spectroscopic data as in Example 15, Method 1. HPLC method (Methods 1 and 2) Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B

45 (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC. Holding time:

10.7 min (3S, 5S-4, R1 = styryl, R4 = t-butyl). 11.1 min (3R, 5S-4, R1 = styryl, R4 = t-butyl). 9.5 min (3a, R1 = styryl).

E11734379

10-19-2015

Example 16: (S) -5-Biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tertbutyl ester (4a, R1 = t-butoxycarbonyl, R4 = hydroxyl).

image80 OH

OR

OR

OR

image81 N

image82

OR

image83

5 To a solution of di-isopropylamine (2.4 g, 24.0 millimoles) in 20 ml of anhydrous tetrahydrofuran, n-butyllithium (8.8 ml, 22.0 millimoles , 2.5 M in hexane) under a N2 atmosphere from -10 ° C to approximately 15 ° C, stir at this temperature for 1 hour, add a solution of (S) -2-biphenyl-4- acid tert-butyl ester yl-methyl5-oxo-pyrrolidine-1-carboxylic (3a, R1 = t-butoxycarbonyl) (7.0 g, 20.0 mmol) in 10 ml anhydrous tetrahydrofuran

10 dropwise, stirred for 1 hour, introduce CO2 for 1 hour, quench with a saturated aqueous solution of NH4Cl, extract with ethyl acetate, wash the combined organic phase with brine, dry over anhydrous sodium sulfate , and the solvent is evaporated in vacuo; The residue is purified by column chromatography to obtain (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tertbutyl ester (4a, R1 = t- butoxycarbonyl, R4 = hydroxyl) ¹H NMR (400 MHz, CDCl3): 1.59 (s, 1H, Boc), 1.85 (m, 1H, 3CHH), 2.36 (m, 1H, 3CHH),

2.48 (m, 1H, 5-CH2), 2.83 (m, 1H, 5-CH2), 3.09 (m, 1H, 2-CH), 4.40 (m, 1H, 4- CH), 6.10 (d, 1H, C = CHH), 7.23 ~ 7.56 (9H, m, aromatic). The ratio of (3S, 5S) to (3R, 5S) is 36:64 as determined by HPLC. Column HPLC method: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Length

20 wave: 210 nm. Temperature: 30 ºC. Holding time:

8.0 min (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = hydroxyl). 8.1 min (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = hydroxy). 25 9.2 min (3a, R1 = t-butoxycarbonyl)

Example 17: (5R) -biphenyl-4-yl-methyl-1- (4-methoxy-benzyl) -3-methylene-pyrrolidin-2-one (1a, R1 = p-methoxy-benzyl).

image84

OMe 30 La (3R / S) -benzoyl- (5S) -biphenyl-4-yl-methyl-1- (4-methoxy-benzyl) -pyrrolidin-2-one (4a, R1 = p-methoxy-benzyl, R4 = phenyl) as a mixture of cis and trans diastereomers (700 mg, 1.47 millimoles) is dissolved in tetrahydrofuran (5 ml), then sodium hydride (60 mg, 1.47 millimoles, 55% in mineral oil) at 0 ºC. After stirring for 15 min, para-formaldehyde (66 mg, 2.2 mmol) is added, the reaction mixture is refluxed for

35 30 min and allowed to cool to room temperature. After addition of NH4Cl (saturated aqueous), the organic layer is separated, washed with brine, dried, and concentrated to give (5R) -biphenyl-4-yl-methyl-1- (4-methoxybenzyl) -3-methylene-pyrrolidin-2-one (1a, R1 = p-methoxy-benzyl). 1 H NMR (400 MHz, CDCl3): 2.46-2.52 (m, 2H), 2.612.67 (m, 1H), 3.13-3.16 (m, 1H), 3.67-3 , 71 (m, 1H), 3.81 (s, 3H), 4.09 (d, J = 14.8 Hz, 1H), 5.15 (d, J = 14.8 Hz, 1H), 5 , 30 (1H, m), 6.02 (1H, m), 7.20 ~ 7.58 (13H, m, aromatic). MS (ESI, m / e) 384 (MH +).

40 HPLC method Column: Eclipse XDB-C18; 150 × 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC.

image85

image86

E11734379

10-19-2015

Retention time: 9.3 min (1a, R1 = p-methoxy-benzyl). Example 18: (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1a, R1 = t-butoxycarbonyl).

image87

10 Method 1

Under N2, the tert-butyl ester of (R / S) -3-benzoyl- (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid (4a, R1 = t -butoxycarbonyl, R4 = phenyl) (1.82 g, 4 mmol) in 5 ml of toluene, added to the sodium hydride mixture (55% in mineral oil, 0.23 g, 5.2 mmol ) in 15 ml of toluene at 0 ° C, and then heated to reflux. Para-formaldehyde (0.25 g, 8 mmol) is added portionwise and refluxed for 2 hours. The reaction mixture is then diluted with 10 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the filtrate is concentrated and purified by column chromatography, eluting with 5: 1 heptane / ethyl acetate, to provide the acid tert-butyl ester.

20 (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic (1a, R1 = t-butoxycarbonyl). Spectroscopic data is as reported in International Publication Number WO2009 / 090251 (Example 23, Method 1).

Method 2

25 The mixture of (R / S) -3-benzoyl- (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid (4a, R1 = tbutoxy-carbonyl , R4 = phenyl) (0.455 g, 1 millimole), para-formaldehyde (60 mg, 2 millimoles), lithium chloride (85 mg, 2 millimoles), and di-isopropyl-ethyl-amine (0.168 g, 1 , 3 mmol) in 5 ml of dry tetrahydrofuran, heated under reflux for 2 hours. The reaction mixture is then diluted with 5 ml of a saturated aqueous solution of chloride of

30 ammonium, and stir for 15 min, stop stirring, and remove the lower aqueous layer. The organic phase is then concentrated in vacuo. Ethyl acetate (10 ml) is added, filtered, and the filtrate is concentrated and purified by column chromatography, eluting with 5: 1 heptane / ethyl acetate, to provide the acid tert-butyl ester (R) - 5-biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid (1a, R1 = t-butoxycarbonyl). Spectroscopic data is as reported in International Publication Number WO2009 / 090251 (Example 23,

35 Method 1).

Method 3

The (R / S) -3-benzoyl- (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester mixture (4a, R1 = t

40 butoxycarbonyl, R4 = phenyl) (0.455 g, 1 mmol), para-formaldehyde (60 mg, 2 mmol), and KOtBu (0.148 g, 1.3 mmol) in 5 ml of dry tetrahydrofuran, heated to reflux for 2 hours. The reaction mixture is then diluted with 5 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (10 ml) is added, filtered, and the filtrate is concentrated and purified by column chromatography, eluting with 5: 1 of

45 heptane / ethyl acetate, to provide the (R) -5-biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl ester (1a, R1 = t-butoxycarbonyl ). Spectroscopic data is as reported in International Publication Number WO2009 / 090251 (Example 23, Method 1).

E11734379

10-19-2015

Method 4

The mixture of (R / S) -3-benzoyl- (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid (4a, R1 = tbutoxycarbonyl, R4 = phenyl) (0.455 g, 1 millimole), para-formaldehyde (60 mg, 2 millimoles), LiCl (85 mg, 2 millimoles), 5 and DBU (0.2 g, 1.3 millimoles) in 5 ml of dry tetrahydrofuran, reflux for 2 hours. The reaction mixture is then diluted with 5 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (10 ml) is added, filtered, and the filtrate is concentrated and purified by column chromatography, eluting with 5: 1 heptane / ethyl acetate, to provide the acid tert-butyl ester (R) - 5-biphenyl-4-yl

10 methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic (1a, R1 = t-butoxycarbonyl). Spectroscopic data is as reported in International Publication Number WO2009 / 090251 (Example 23, Method 1).

Method 5

15 The mixture of (R / S) -3-benzoyl- (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid (4a, R1 = tbutoxy-carbonyl , R4 = phenyl) (0.455 g, 1 millimole), formaldehyde (37% in water, 0.24 g, 3 millimoles), tetrabutyl ammonium hydroxide (6.5 mg, 0.01 millimoles), and K2CO3 ( 0.28 g, 1.3 mmol, dissolved in 1 milliliter of water) in 5 ml of dry tetrahydrofuran, heated to 50 ° C, and stirred for 2 hours. The reaction mixture is then diluted with 5 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The phase

Organic 20 is then concentrated in vacuo. Ethyl acetate (10 ml) is added, filtered, and the filtrate is concentrated and purified by column chromatography, eluting with 5: 1 heptane / ethyl acetate, to provide the acid tert-butyl ester (R) - 5-biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid (1a, R1 = t-butoxycarbonyl). Spectroscopic data is as reported in International Publication Number WO2009 / 090251 (Example 23, Method 1).

25 Method 6

The mixture of (R / S) -3-benzoyl- (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid (4a, R1 = tbutoxycarbonyl, R4 = phenyl) (0.45 g, 1 millimole), para-formaldehyde (60 mg, 2 millimoles), and potassium tert-butoxide 30 (0.148 g, 1.3 millimoles) in 5 ml 1,2-dimethoxy- Dry ethane (DME), stir for 2 hours at 20 ° C. The reaction mixture is then diluted with 5 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (10 ml) is added, filtered, and the filtrate is concentrated and purified by column chromatography, eluting with 5: 1 heptane / ethyl acetate, to provide the acid tert-butyl ester (R) - 5-biphenyl-4-yl

Methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic (1a, R1 = tert-butoxycarbonyl). Spectroscopic data is as reported in International Publication Number WO2009 / 090251 (Example 23, Method 1).

Example 19: (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl ester (1a, R1 = t-butoxycarbonyl).

40

image88

The mixture of (R / S) -3-acetyl- (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid (4a, R1 = tbutoxy-carbonyl, R4 = methyl) (0.79 g, 2 mmol), formaldehyde (37% in water, 0.49 g, 6 mmol), tetrabutyl-ammonium hydroxide (26 mg, 0.1 mmol), and K2CO3 ( 0.55 g, 1.3 mmol, dissolved in 2 ml of water) in 10 ml of dry tetrahydrofuran, heated to 50 ° C, and stirred for 2 hours. The reaction mixture is then diluted with 10 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the filtrate is concentrated and purified by column chromatography, eluting with 5: 1 heptane / ethyl acetate, to provide the

(R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl ester (1a, R1 = tertbutoxycarbonyl). Spectroscopic data is as reported in International Publication Number WO2009 / 090251 (Example 23, Method 1).

E11734379

10-19-2015

Example 20: (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl ester (1a, R1 = tertbutoxycarbonyl).

image89

The mixture of (R / S) -3-isobutyryl- (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4a, R1 = tbutoxy-carbonyl, R4 = isopropyl) (0.84 g, 2 mmol), formaldehyde (37% in water, 0.49 g, 6 mmol), tetrabutyl-ammonium hydroxide (26 mg, 0.1 mmol), and K2CO3 (0 , 55 g, 1.3 mmol, dissolved in 2 ml of water) in 10 ml of dry tetrahydrofuran, heated to 50 ° C, and stirred for 2 hours. The reaction mixture is then diluted with 10 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the filtrate is concentrated and purified by column chromatography, eluting with 5: 1 heptane / ethyl acetate, to provide the acid tert-butyl ester (R) - 5-biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic (1a, R1 = t-butoxycarbonyl). Spectroscopic data is as reported in International Publication Number

15 WO2009 / 090251 (Example 23, Method 1).

Example 21: (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl ester (1a, R1 = t-butoxycarbonyl).

image90

The (R / S) -3- (2,2-dimethyl-propionyl) - (S) -5-biphenyl-4-yl-methyl-2-oxo-pyrrolidin-1 acid tert-butyl ester mixture

carboxylic 4a, R1 = t-butoxycarbonyl, R4 = t-butyl) (0.87 g, 2 mmol), formaldehyde (37% in water, 0.49 g, 6

mmol), tetrabutyl ammonium hydroxide (26 mg, 0.1 mmol), and K2CO3 (0.55 g, 1.3 mmol, dissolved in 2 ml of water) in 10 ml of dry tetrahydrofuran, heated to 50 ° C, and stir for 2 hours. Then the mixture of

The reaction is diluted with 10 ml of brine, and stirred for 15 min, stirring is discontinued, and the layer is removed.

lower watery. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the

The filtrate is concentrated and purified by column chromatography, eluting with 5: 1 heptane / ethyl acetate,

to provide (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1a, R1 = t30-butoxycarbonyl). Spectroscopic data is as reported in International Publication Number

WO2009 / 090251 (Example 23, Method 1).

E11734379

10-19-2015

Example 22: (R) -5-Biphenyl-4-yl-methyl-3-methylene-1-pyrrolidin-1-yl-methyl-pyrrolidin-2-one (1a, R1 = pyrrolidinyl-methyl).

image91

5 The mixture of (R / S) -3-benzoyl- (S) -5-biphenyl-4-yl-methyl-1-pyrrolidin-1-yl-methyl-pyrrolidin-2-one (4a, R1 = pyrrolidinyl -methyl, R4 = phenyl) (0.44 g, 1 millimole), formaldehyde (37% in water, 0.24 g, 3 millimoles), TBAH (6.5 mg, 0.01 millimoles), and K2CO3 (0.28 g, 1.3 mmol, dissolved in 1 milliliter water) in 5 ml of dry tetrahydrofuran, heated to 50 ° C, and stirred for 2 hours. The reaction mixture is then diluted with 5 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. I know

10 Add ethyl acetate (10 ml), filter, and the filtrate is concentrated and purified by column chromatography, eluting with 5: 1 heptane / ethyl acetate, to provide (R) -5-biphenyl-4 -yl-methyl-3-methylene-1-pyrrolidin-1-ylmethyl-pyrrolidin-2-one (1a, R1 = pyrrolidinyl-methyl). ¹H NMR (400 MHz, CDCl3): 1.68 (m, 4H, 2xCH2CH2), 2.06 (m, 1H, 3-CHH), 2.31 (m, 1H, 3-CHH), 2.51 ( m, 4H, 2xNCH2), 2.67 (d, 1H, 5-CHH), 2.65 (dd, 1H, N-CHH), 3.15 (dd, 1H, N-CHH), 2.92 ( d, 1H, 5-CHH), 4.01 (m, 1H, 4-CH), 5.54 (d, 1H, = CHH), 6.02 (d, 1H, = CHH), 7.20- 7.80 (14H, m,

15 aromatic). Column HPLC method: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (90% B); 10 min (95% of B); 15 min (95% of B). Flow rate: 0.7 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC.

20 Retention time:

8.1 min (1a, R1 = pyrrolidinyl-methyl).

Example 23: (R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl). 25

image92

image93

image94

Method 1

30 La (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl) (0.50 g, 1.1 mmol) is dissolved in 2 ml of anhydrous toluene, sodium hydride (65 mg, 1.5 mmol) is added in portions, then paraformaldehyde (66 mg, 2.2 mmol) in one portion, and the Resulting mixture is heated to reflux for 4 hours under a nitrogen atmosphere. The reaction mixture is cooled to room temperature, then quenched with a saturated aqueous NH4Cl solution, extracted with toluene, the organic extracts are washed with a

35 saturated aqueous Na2CO3 solution and brine, dried over anhydrous Na2SO4, and evaporated the solvent in vacuo, to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl), which could be used in the next step directly. ¹H NMR (400 MHz, CDCl3): 2.68 (m, 2H, 3-CHH + 5-CH2H), 2.81 (m, 1H, 3-CHH), 3.28 (m, 1H, 5-CH2H) , 4.32 (m, 1H, 4-CH), 5.35 (s, 1H, C = CHH), 6.04 (s, 1H, C = CHH), 6.23 (d, 1H, C = CHH), 7.21 ~ 7.72 (m, 15H, aromatic + C = CHH).

E11734379

10-19-2015

Method 2

(S) -3-Benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl) (0.50 g , 1.1 mmol) is dissolved in 2 ml of anhydrous tetrahydrofuran, potassium tertbutoxide (161 mg, 1.4 mmol) are added, and to

5 formaldehyde (66 mg, 2.2 mmol) in one portion, and the resulting mixture was refluxed for 2 hours under a nitrogen atmosphere. The reaction mixture is cooled to room temperature, 15 ml of water are added, extracted with toluene, the organic extracts are washed with a saturated aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, the solvent is evaporated in vacuo, to obtain the crude product, which is purified by column chromatography to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl). Spectroscopic data as in Example 23, Method 1.

Method 3

(S) -3-Benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl) (0.50 g , 1.1 millimoles)

15 is dissolved in 2 ml of anhydrous tetrahydrofuran, potassium tert-butoxide (161 mg, 1.4 mmol) and paraformaldehyde (66 mg, 2.2 mmol) are added in one portion, and the resulting mixture is stirred at room temperature during mixing. night under a nitrogen atmosphere. 15 ml of water are added to the reaction mixture, it is extracted with toluene, the organic extracts are washed with a saturated aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, and the solvent is evaporated in vacuo; the residue is purified by column chromatography to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl ). Spectroscopic data as in Example 23, Method 1.

Method 4

25 La (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl) (0.50 g, 1.1 mmol) is dissolved in 2 ml of methanol, morpholine (125 mg, 1.4 mmol) and para-formaldehyde (66 mg, 2.2 mmol) are added in one portion, and refluxed for 2 hours under a nitrogen atmosphere. 10 ml of 5% HCl (aqueous) are added to the reaction mixture, it is extracted with toluene, the organic extracts are washed with a saturated aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, and the solvent is evaporated to the vacuum; the residue is purified by column chromatography to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-1 ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl) . Spectroscopic data as in Example 23, Method 1.

Method 5

35 La (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl) (54.3 g, 118.8 mmol) is dissolved in 120 ml of anhydrous tetrahydrofuran, para-formaldehyde (4.28 g, 142.6 mmol), iPr2NEt (20.0 g, 154.5 mmol), and lithium chloride are added anhydrous (2.56 g, 59.4 mmol), and refluxed for 2 hours under a nitrogen atmosphere. The reaction mixture is cooled to room temperature, 200 ml of toluene are added, washed with 5% HCl (aqueous), saturated Na2CO3 and brine, dried over anhydrous Na2SO4, and the solvent is evaporated in vacuo, to give the (R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl). Spectroscopic data as in Example 23, Method 1.

Method 6

45 La (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl) (1.0 g, 2.2 mmol) is dissolved in 5 ml of anhydrous tetrahydrofuran, para-formaldehyde (80 mg, 2.6 mmol), triethylamine (288 mg, 2.8 mmol), and anhydrous lithium chloride ( 186 mg, 4.4 mmol), and refluxed overnight under a nitrogen atmosphere. The reaction mixture is cooled to room temperature, 20 ml of toluene are added, washed with 5% HCl (aqueous), saturated Na2CO3 and brine, dried over anhydrous Na2SO4, and the solvent is evaporated in vacuo, to give the (R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl). Spectroscopic data as in Example 23, Method 1.

Method 7

55 La (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl) (1.0 g, 2.2 mmol) is dissolved in 5 ml of anhydrous tetrahydrofuran, para-formaldehyde (80 mg, 2.6 mmol), DBU (434 mg, 2.8 mmol), and anhydrous lithium chloride (186 mg , 4.4 mmol), and refluxed overnight under a nitrogen atmosphere. The reaction mixture is cooled to room temperature, 20 ml of toluene are added, washed with 5% HCl (aqueous), saturated Na2CO3 and brine, dried over anhydrous Na2SO4, and the solvent is evaporated in vacuo, to give the (R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl). Spectroscopic data as in Example 23, Method 1.

Method 8

65 La (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl) (1.0 g, 2.2 mmol) is dissolved in 5 ml of anhydrous tetrahydrofuran, an aqueous solution of 37% formaldehyde (0.36 ml,

E11734379

10-19-2015

4.4 mmol), an aqueous solution of 1M K2CO3 (4.4 ml, 4.4 mmol), and n-Bu4NOH (12 mg, 0.05 mmol), is heated to 40 ° C for 2 hours. The reaction mixture is cooled to room temperature, extracted with ethyl acetate, the extracts are washed with a saturated aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo; the residue is purified by column chromatography to obtain (R) -5

5-biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl). Spectroscopic data as in Example 23, Method 1.

Method 9

10 La (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl) (1.0 g, 2.2 mmol) is dissolved in 5 ml of anhydrous tetrahydrofuran, iPr2NEt (370 mg, 2.8 mmol), anhydrous lithium chloride (49 mg, 1.1 mmol), and anhydrous Na2SO4 (260 mg, 2.2 mmol), reflux for 30 min under a nitrogen atmosphere, then para-formaldehyde (80 mg, 2.7 mmol) is added, and reflux for 2 hours under a nitrogen atmosphere. The reaction mixture is cooled to room temperature, 20 ml are added

15 of toluene and 10 ml of 5% HCl (aqueous), the aqueous phase is separated, washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo, to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl). Spectroscopic data as in Example 23, Method 1.

20 Method 10

(S) -3-Benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl) (1.0 g , 2.2 mmol) is dissolved in 5 ml of anhydrous tetrahydrofuran, iPr2NEt (370 mg, 2.8 mmol), anhydrous lithium chloride (49 mg, 1.1 mmol), and anhydrous MgSO4 (260 mg, 2 , 2 mmol), reflux for 30 min under a

25 nitrogen atmosphere, then para-formaldehyde (80 mg, 2.7 mmol) is added, and refluxed for 2 hours under nitrogen atmosphere. The reaction mixture is cooled to room temperature, 20 ml of toluene and 10 ml of 5% HCl (aqueous) are added, the aqueous phase is separated, washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, Dry over anhydrous sodium sulfate, and concentrate in vacuo, to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one ( 1a, R1 = styryl).

30 Method 11

(S) -3-Benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = styryl, R4 = phenyl) (10.0 g , 21.9 mmol) is dissolved in 50 ml of anhydrous tetrahydrofuran, iPr2NEt (3.7 g, 28.5 mmol), anhydrous lithium chloride 35 (490 mg, 11.0 mmol), and molecular sieves (2 , 0 grams), reflux for 30 min under a nitrogen atmosphere, then para-formaldehyde (790 mg, 26.3 mmol) is added, and reflux for 2 hours under a nitrogen atmosphere. The reaction mixture is cooled to room temperature, 100 ml of toluene are added, it is filtered to remove the molecular sieves, the filtration is washed with 5% HCl (aqueous) (50 ml, 2 times), saturated Na2CO3 and brine, dry over anhydrous Na2SO4, and concentrate in vacuo, to obtain (R) -5-biphenyl-4

40 yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl), which is used directly in the next step. Spectroscopic data as in Example 23, Method 1. HPLC method (Methods 1-11) Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Length

45 wave: 210 nm. Temperature: 30 ºC. Holding time:

10.2 min (1a, R1 = styryl).

50 Example 24: (R) -5-biphenyl-4-yl-methyl-1 - ((E) -but-1-enyl) -3-methylene-pyrrolidin-2-one (1a, R1 = 1-butenyl) .

image95

OR

image96 OR

image97

image98

E11734379

10-19-2015

Method 1

A suspension of sodium hydride (2.03 g, 46.3 mmol) in 40 ml of anhydrous toluene is cooled to 0 ° C by means of an ice bath, a solution of (S) -3-benzoyl-5-biphenyl is added -4-yl-methyl-1 - ((E) -but-1-enyl) -pyrrolidin-2-one (4a, R1 5 = 1-butenyl, R4 = phenyl) (14.7 g, 35.7 mmol ) in anhydrous toluene dropwise, stir for 30 min, then add para-formaldehyde (2.2 g, 71.4 mmol) in portions, heat to reflux under a nitrogen atmosphere for 4 hours, cool to room temperature, quenched with a saturated aqueous solution of NH4Cl, extracted with toluene, the combined organic extracts are washed with a saturated aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4 and concentrated, to obtain the (R) - 5-biphenyl-4-yl-methyl-1 - ((E) -but-1-enyl)

10 3-methylene-pyrrolidin-2-one (1a, R1 = 1-butenyl). ¹H NMR (400 MHz, CDCl3): 1.07 (t, 3H, CH3H), 2.12 (m, 2H, CH2H), 2.57 (m, 2H, 3-CH2), 2.65 (m , 1H, 5-CH2), 3.16 (m, 1H, 5-CH2), 4.14 (m, 1H, 4-CH), 5.22 (s, 1H, C = CHH), 5, 27 (m, 1H, CH = CH), 5.91 (d, 1H, HC = CHH), 6.85 (d, 1H, HC = CH-N), 7.14 ~ 7.51 (9H, m, aromatic).

Method 2

15 To a solution of (S) -3-benzoyl-5-biphenyl-4-yl-methyl-1 - ((E) -but-1-enyl) -pyrrolidin-2-one (4a, R1 = 1- butenyl, R4 = phenyl) (5.5 g, 13.2 mmol) in 25 ml of tetrahydrofuran, an aqueous solution of 1 M K2CO3 (26.4 ml, 26.4 mmol), an aqueous solution of CH2O at 37% (2.2 ml, 26.4 mmol), and n-Bu4NOH (0.4 ml, 0.7 mmol), heated to 45 ° C under N2 atmosphere for 2 hours, cooled to room temperature, is removed

20 with toluene, the combined organic layer is washed with 5% HCl (aqueous), a saturated aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, the solvent is evaporated, and the residue is purified by column chromatography to obtain (R) -5-biphenyl-4-yl-methyl-1 - ((E) -but-1-enyl) -3-methylene-pyrrolidin-2-one (1a, R1 = 1-butenyl). Spectroscopic data as in Example 24, Method 1. HPLC method (Methods 1 and 2)

25 Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC. Holding time:

9.9 min (1a, R1 = 1-butenyl).

Example 25: (R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl).

OR

image99 OR

N

image100

image101

image102

35 La (S) -5-biphenyl-4-yl-methyl-3-isobutyryl-1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = t-butoxycarbonyl, R4 = isopropyl) (2.5 g, 6.2 mmol) is dissolved in 10 ml of anhydrous tetrahydrofuran, iPr2NEt (1.1 g, 8.2 mmol), anhydrous LiCl (140 mg, 3.2 mmol), and molecular sieves are added (0.5 grams); The mixture is refluxed under a nitrogen atmosphere for 30 min, then para-formaldehyde (230 mg, 7.6 mmol) is added in one portion, and

40, reflux for 2 hours, cool to room temperature, add 50 ml of toluene, filter, the filtration is washed with 10% HCl (aqueous), saturated Na2CO3 and brine, dried over anhydrous NaSO4, and evaporates in vacuo; the residue is purified by column chromatography to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-1 ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl) . Spectroscopic data as in Example 23, Method 1.

Four. Five

E11734379

10-19-2015

Example 26: (R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl).

OR

NO

image103

image104

image105

Image106

5 La (S) -5-biphenyl-4-yl-methyl-3- (2,2-dimethyl-propionyl) -1 - ((E) -styryl) -pyrrolidin-2-one (4a, R1 = t- butoxycarbonyl, R4 = t-butyl) (2.7 g, 6.2 mmol) is dissolved in 10 ml of anhydrous tetrahydrofuran, iPr2NEt (1.1 g, 8.2 mmol), anhydrous LiCl (140 mg, 3 , 2 mmol), and molecular sieves (0.5 grams), the mixture is refluxed under a nitrogen atmosphere for 30 min, then para-formaldehyde (230 mg, 7.6 mmol) is added in one portion, and reflux for 2 hours, cool to room temperature, add 50 ml of toluene,

10 filtered, the filtration is washed with 10% HCl (aqueous), saturated Na2CO3 and brine, dried over anhydrous NaSO4, and evaporated in vacuo; The residue is purified by column chromatography to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl). Spectroscopic data as in Example 23, Method 1.

Example 27: (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl ester (1a, R1 = t-butoxycarbonyl).

image107 OH O

OR image108 OR image109 N

O O

Biphenyl-4-yl-methyl-2-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tertbutyl ester (4a, R1 = t-butoxycarbonyl, R4 =

20 hydroxyl) (3.95 g, 10.0 mmol) is dissolved in 10 ml of methanol, para-formaldehyde (0.60 g, 20.0 mmol) are added, and morpholine (1.05 g, 12.0 millimoles), the mixture is refluxed for 2 hours under a nitrogen atmosphere, cooled to room temperature, and the solvent is evaporated in vacuo; The residue is dissolved in 50 ml of ethyl acetate, washed with 1% HCl (aqueous), 10% sodium hydrogen carbonate (aqueous), and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo , to obtain (R) -5-biphenyl-4-yl-methyl acid tert-butyl ester

3-methylene-2-oxo-pyrrolidine-1-carboxylic (1a, R1 = tert-butoxycarbonyl). ¹H NMR (400 MHz, CDCl3): 1.62 (s, 9H, (CH3) 3), 2.56 (m, 1H, 3-CHH), 2.60 (m, 1H, 3CHH), 2.70 (d, 1H, 5-CHH), 3.26 (d, 1H, 5-CHH), 4.43 (m, 1H, 4-CH), 5.45 (d, 1H, C = CHH), 6 , 17 (d, 1H, C = CHH), 7.20 ~ 7.60 (9H, m, aromatic); m / z (+ ESI) 381 ([MNa] +, 7%), 364 ([MH] +, 12), 308 (100), 264 (10). HPLC method

Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC. Retention time: 9.7 min (1a, R1 = t-butoxycarbonyl).

35

E11734379

10-19-2015

Example 28: (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl ester (1a, R1 = t-butoxycarbonyl).

image110

image111

5 Method 1

Under N2 atmosphere, add n-butyllithium (56 ml, 2.5 M in hexane, 0.14 mol) to the mixture of HMDS (24.2 g, 0.15 mol) in 300 ml of dry tetrahydrofuran at -10 ° C, and the resulting mixture is then stirred for 30 min at 10-10 ° C. A mixture of (S) -2-biphenyl-4-yl-methyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3a, R1 = t-butoxycarbonyl) (35.1 g, 0.1 mol) in 50 ml of dry tetrahydrofuran to the reaction mixture at -10 ° C; after about 30 min, n-butyllithium (40 ml, 2.5 M in hexane, 0.1 mol) is added to the reaction mixture at 10 ° C, and the resulting mixture is then stirred for 30 min at - 10 ° C. Benzoyl chloride (15.5 g, 0.11 mol) is added to the reaction mixture at -10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 100 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. Formaldehyde (37% in water, 24.3 g, 0.3 mol), an aqueous solution of K2CO3 (27.6 grams in 100 ml of water, 0.2 mol), and a solution of tetrabutylammonium hydroxide are added. (40% in water, 1.3 g, 5 mmol) to the remaining organic phase, and heated to 50 ° C, and stirred for 2 hours. The reaction mixture is then diluted with 100 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (200 ml) is added, filtered, and the filtrate is concentrated to give (R) -5-biphenyl-4-yl-methyl-3-methylene-2oxo-pyrrolidine-1 acid tertbutyl ester. -carboxylic (1a, R1 = t-butoxycarbonyl). The crude (R) -5-biphenyl-4-yl-methyl-3-methylene-2oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1a, R1 = t-butoxycarbonyl) is purified by column chromatography, eluting with 3: 1 heptane / ethyl acetate. ¹H NMR (400 MHz, CDCl3): 1.62 (s, 9H, (CH3) 3), 2.56 (m, 1H, 3-CHH),

2.60 (m, 1H, 3CHH), 2.70 (d, 1H, 5-CHH), 3.26 (d, 1H, 5-CHH), 4.43 (m, 1H, 4-CH) , 5.45 (d, 1H, C = CHH), 6.17 (d, 1H, C = CHH), 7.20 ~ 7.60 (9H, m, aromatic); m / z (+ ESI) 381 ([MNa] +, 7%), 364 ([MH] +, 12), 308 (100), 264 (10). The ratio of Intermediate (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) to (3R, 5S -4, R1 = tert-butoxycarbonyl, R4 = phenyl) is 70: 30, as determined by HPLC.

30 Method 2

Under N2 atmosphere, n-butyllithium (56 ml, 2.5 M in hexane, 0.14 mol) is added to the di-isopropylamine mixture (14.2 g, 0.15 mol) in 300 ml of dry tetrahydrofuran at -10 ° C, and the resulting mixture is then stirred for 30 min at -10 ° C. A mixture of (S) -2-biphenyl-4-yl-methyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester 35 (3a, R1 = t-butoxycarbonyl) (35.1 g 0.1 mol) in 50 ml of dry tetrahydrofuran to the reaction mixture at -10 ° C; after about 30 min, n-butyllithium (40 ml, 2.5 M in hexane, 0.1 mol) is added to the reaction mixture at -10 ° C, and the resulting mixture is then stirred for 30 min at -10 ° C. Benzoyl chloride (15.5 g, 0.11 mol) is added to the reaction mixture at -10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 100 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. Formaldehyde (37% in water, 24.3 g, 0.3 mol), an aqueous solution of K2CO3 (27.6 grams in 100 ml of water, 0.2 mol), and a tetrabutyl hydroxide solution are added. -ammonium (40% in water, 1.3 g, 5 mmol) to the remaining organic phase, and heated to 50 ° C, and stirred for 2 hours. The reaction mixture is then diluted with 100 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (200 ml) is added, filtered, and the filtrate is concentrated to give (R) -5-biphenyl-4-methyl-3-methylene-2-oxo-pyrrolidine acid tert-butyl ester. 1-carboxylic (1a, R1 = t-butoxycarbonyl). Crude (R) -5-Biphenyl-4yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl ester (1a, R1 = t-butoxycarbonyl) can be purified by column chromatography , eluting with 3: 1 heptane / ethyl acetate. The ratio of Intermediate (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) to (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) is 70: 30, as it is determined

50 by HPLC. Spectroscopic data as in Example 28, Method 1.

Method 3

Under N2 atmosphere, add LHMDS (25 ml, 1.0 M in tetrahydrofuran, 25 mmol) to the tert-butyl ester mixture.

55 of (S) -2-Biphenyl-4-yl-methyl-5-oxo-pyrrolidine-1-carboxylic acid (3a, R1 = t-butoxycarbonyl) (3.51 g, 10 mmol) in 20 ml of dry tetrahydrofuran, and added to the reaction mixture at -10 ° C, and the resulting mixture was then stirred

E11734379

10-19-2015

for 30 min at -10 ° C. Benzoyl chloride (1.55 g, 11 mmol) is added to the reaction mixture at -10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 15 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. Formaldehyde (37% in water, 2.43 g, 0.03 mol), an aqueous solution of K2CO3 (2.76 5 grams in 10 ml of water, 0.02 mol), and a solution of hydroxide of tetrabutyl ammonium (40% in water, 0.13 g, 0.5 mmol) to the remaining organic phase, and heat to 50 ° C, and stir for 2 hours. The reaction mixture is then diluted with 15 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the filtrate is concentrated to give (R) -5-biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine acid tert-butyl ester. -1-carboxylic

10 (1a, R1 = t-butoxycarbonyl). The crude (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1a, R1 = t-butoxycarbonyl) can be purified by chromatography column, eluting with 3: 1 heptane / ethyl acetate. The ratio of Intermediate (3S, 5S-4a, R1 = tert-butoxycarbonyl, R4 = benzyl) to (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) is 70: 30, as determined by HPLC. Spectroscopic data as in Example 28, Method 1.

15 Method 4

Under N2 atmosphere, add LDA (25 ml, 1.0 M in tetrahydrofuran, 25 mmol) to the mixture of (S) -2-biphenyl-4-yl-methyl-5-oxo-pyrrolidine acid tert-butyl ester. -1-carboxylic (3a, R1 = t-butoxycarbonyl) (3.51 g, 10 mmol) in 20 ml

20 of dry tetrahydrofuran, and added to the reaction mixture at -10 ° C, and the resulting mixture was then stirred for 30 min at -10 ° C. Benzoyl chloride (1.55 g, 11 mmol) is added to the reaction mixture at -10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 15 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. Formaldehyde (37% in water, 2.43 g, 0.03 mol), an aqueous solution of K2CO3 (2.76

25 grams in 10 ml of water, 0.02 mol), and a solution of tetrabutyl-ammonium hydroxide (40% in water, 0.13 g, 0.5 mmol) to the remaining organic phase, and heated to 50 ° C, and stir for 2 hours. The reaction mixture is then diluted with 15 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the filtrate is concentrated to give (R) -5-biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine acid tert-butyl ester. -1-carboxylic

30 (1a, R1 = t-butoxycarbonyl). The crude (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1a, R1 = t-butoxycarbonyl) can be purified by chromatography column, eluting with 3: 1 heptane / ethyl acetate. The ratio of Intermediate (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) to (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) is 70: 30, as determined by HPLC. Spectroscopic data as in Example 28, Method 1.

35 HPLC method (Methods 1-4) Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC. Holding time:

40 9.7 min (1a, R1 = t-butoxycarbonyl).

Example 29: (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl ester (1a, R1 = t-butoxycarbonyl)

Four. Five

image112

image113

image114

Under N2 atmosphere, add LHMDS (12.5 ml, 1.0 M in tetrahydrofuran, 12.5 mmol) to the (S) -2-biphenyl-4-yl-methyl-5-oxo acid tert-butyl ester mixture. -pyrrolidine-1-carboxylic (3a, R1 = t-butoxy-carbonyl) (1.76 g, 5 mmol) 50 in 15 ml of dry tetrahydrofuran, and added to the reaction mixture at -10 ° C, and the mixture The resulting mixture is then stirred for 30 min at -10 ° C. Acetyl chloride (0.47 g, 6 mmol) is added to the reaction mixture at 10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 10 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. Formaldehyde (37% in water, 1.2 g, 15 mmol), an aqueous solution of K2CO3 (1.4 55 grams in 5 ml of water, 0.01 mol), and a solution of tetrabutyl hydroxide are added. ammonium (40% in water, 0.06 g, 0.25 mmol) to the remaining organic phase, and heat to 50 ° C, and stir for 2 hours. Then the mixture of

E11734379

10-19-2015

The reaction is diluted with 10 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the filtrate is concentrated to give (R) -5-biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine acid tert-butyl ester. -1-carboxylic (1a, R1 = t-butoxycarbonyl). (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl-ester

Crude 5 (1a, R1 = t-butoxycarbonyl) can be purified by column chromatography, eluting with 3: 1 heptane / ethyl acetate. The ratio of Intermediate (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = methyl) to (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = methyl) is 70: 30, as determined by HPLC. Spectroscopic data as in Example 28, Method 1.

10 Example 30: (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl ester (1a, R1 = t-butoxycarbonyl)

image115

Image116

image117

15 Under N2 atmosphere, add LHMDS (12.5 ml, 1.0 M in tetrahydrofuran, 12.5 mmol) to the (S) -2-biphenyl-4-yl-methyl-5- oxo-pyrrolidine-1-carboxylic (3a, R1 = t-butoxy-carbonyl) (1.76 g, 5 mmol) in 15 ml of dry tetrahydrofuran, and added to the reaction mixture at -10 ° C, and the mixture The resulting mixture is then stirred for 30 min at -10 ° C. 2,2-Dimethyl-propionyl chloride (0.72 g, 6 mmol) is added to the reaction mixture at -10 ° C; After approximately 1 hour at -10 ° C, the reaction mixture is diluted with 10 ml of a

20 saturated aqueous ammonium chloride solution, and stir for 15 min, stop stirring, and remove the lower aqueous layer. Formaldehyde (37% in water, 1.2 g, 15 mmol), an aqueous solution of K2CO3 (1.4 grams in 5 ml of water, 0.01 mol), and a solution of tetrabutyl-ammonium hydroxide are added. (40% in water, 0.06 g, 0.25 mmol) to the remaining organic phase, and heated to 50 ° C, and stirred for 2 hours. Then the reaction mixture is diluted with 10 ml of brine, and stirred for 15 min, stirring is discontinued, and

25 removes the lower aqueous layer. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the filtrate is concentrated to give (R) -5-biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine acid tert-butyl ester. -1 carboxylic (1a, R1 = t-butoxycarbonyl). The crude (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl ester (1a, R1 = t-butoxycarbonyl) can be purified by column chromatography , eluting with

3: 1 heptane / ethyl acetate. The ratio of Intermediate (3S, 5S-4, R1 = t-butoxy-carbonyl, R4 = t-butyl) to

30 (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = t-butyl) is 80:20, as determined by HPLC. Spectroscopic data as in Example 28, Method 1.

Example 31: (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl ester (1a, R1 = t-butoxycarbonyl)

35

image118

image119

image120

Under N2 atmosphere, add LHMDS (12.5 ml, 1.0 M in tetrahydrofuran, 12.5 mmol) to the (S) -2-biphenyl-4-yl-methyl-5-oxo acid tert-butyl ester mixture. -pyrrolidine-1-carboxylic (3a, R1 = t-butoxy-carbonyl) (1.76 g, 5 mmol) 40 in 15 ml of dry tetrahydrofuran, and added to the reaction mixture at -10 ° C, and the mixture The resulting mixture is then stirred for 30 min at -10 ° C. Isobutyryl chloride (0.64 g, 6 mmol) is added to the reaction mixture at 10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 10 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. Formaldehyde (37% in water, 1.2 g, 15 mmol), an aqueous solution of K2CO3 (1.445 grams in 5 ml of water, 0.01 mol), and a solution of tetrabutyl hydroxide are added. ammonium (40% in water, 0.06 g, 0.25 mmol) to the remaining organic phase, and heat to 50 ° C, and stir for 2 hours. Then the mixture of

E11734379

10-19-2015

The reaction is diluted with 10 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. The organic phase is then concentrated in vacuo. Ethyl acetate (20 ml) is added, filtered, and the filtrate is concentrated to give (R) -5-biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine acid tert-butyl ester. -1-carboxylic (1a, R1 = t-butoxycarbonyl). (R) -5-Biphenyl-4-yl-methyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tertbutyl-ester

Crude 5 (1a, R1 = t-butoxycarbonyl) can be purified by column chromatography, eluting with 3: 1 heptane / ethyl acetate. The ratio of Intermediate (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = isopropyl) to (3R, 5S4, R1 = t-butoxycarbonyl, R4 = isopropyl) is 70: 30, as determined by HPLC. Spectroscopic data as in Example 28, Method 1.

10 Example 32: (R) -5-biphenyl-4-yl-methyl-3-methylene-pyrrolidin-2-one (1a, R1 = H)

image121

image122

(R) -5-Biphenyl-4-yl-methyl-3-methylene-1-pyrrolidin-1-yl-methyl-pyrrolidin-2-one (1a, R1 = pyrrolidinyl-methyl) (0.35 g, 1 millimole)

15 is mixed with a mixture of acetic acid and concentrated hydrochloric acid (10 ml, ratio 1: 1), and stirred under reflux for approximately 3 hours. The solution is then concentrated in vacuo, and the residue is purified by column chromatography, eluting with 1: 1 heptane / ethyl acetate, to give (R) -5-biphenyl-4-yl-methyl-3-methylene-pyrrolidine. -2-one (1a, R1 = H). ¹H NMR (400 MHz, CDCl3): 2.58 (m, 1H, 3-CHH), 2.76 (m, 1H, 3CHH), 2.90 (dd, 1H, 5-CHH), 2.99 ( dd, 1H, 5-CHH), 3.92 (m, 1H, 4-CH), 5.37 (d, 1H, C = CHH), 6.01 (d, 1H, C = CHH), 7, 20 ~ 7.60

20 (9H, m, aromatic). Column HPLC method: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC.

25 Retention time:

6.7 min (1a, R1 = H).

Example 33: (R) -5-Biphenyl-4-yl-methyl-1 - ((E) -but-1-enyl) -3-methylene-pyrrolidin-2-one (1a, R1 = H) 30

O N

image123 OR

image124

image125

(R) -5-Biphenyl-4-yl-methyl-1 - ((E) -but-1-enyl) -3-methylene-pyrrolidin-2-one (1a, R1 = 1-butenyl) (11, 5 g, 35.6 mmol) is dissolved in 100 ml of toluene, 35 ml of concentrated HCl are added, refluxed under N2 atmosphere for

For 5 hours, cool to room temperature, separate the aqueous phase, wash with an aqueous sodium hydrogen carbonate solution and brine, dry over anhydrous Na2SO4, and concentrate in vacuo; The residue is recrystallized from toluene / tert-butyl-methyl-ether = 1: 3 to about 1: 4, to give (R) -5-biphenyl-4-yl-methyl-1 - ((E) -but -1-enyl) 3-methylene-pyrrolidin-2-one (1a, R1 = H). Spectroscopic data as in Example 32.

40

E11734379

10-19-2015

Example 34: (R) -5-Biphenyl-4-yl-methyl-3-methylene-pyrrolidin-2-one (1a, R1 = H)

O N

image126

image127 OR

image128

5 Method 1

(R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl) (1.0 g, 2.7 millimoles) is dissolved in 10 ml of ethanol, concentrated HCl (5 ml) is added, and refluxed under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, and concentrated in vacuo; The residue is extracted with toluene, the organic phase is washed with a saturated aqueous solution of Na2SO3, an aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, and the solvent is evaporated in vacuo, to obtain the crude product, the which is recrystallized from toluene / tert-butyl-methyl-ether = 1: 3 to about 1: 4, to give (R) -5-biphenyl-4-ylmethyl-3-methylene-pyrrolidin-2-one (1a , R1 = H). ¹H NMR (400 MHz, CDCl3): 2.56 (m, 1H, 3-CHH), 2.77 (m, 1H, 5-CHH), 2.89 (m, 1H, 5-CHH), 3, 03 (m, 1H, 3-CHH), 3.92 (m, 1H, 4-CH), 5.36 (s, 1H, C = CHH), 6.01 (s, 1H, C = CHH), 6.32 (s,

1H, NHH), 7.24 ~ 7.58 (m, 9H, aromatic).

Method 2

(R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl) (1.0 g, 2.7 millimoles) dissolves

20 in 10 ml of toluene, add concentrated HCl (5 ml), and reflux under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, and concentrated in vacuo; the residue is extracted with toluene, the organic phase is washed with a saturated aqueous solution of Na2SO3, an aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, and the solvent is evaporated in vacuo; The residue is purified by column chromatography to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-pyrrolidin-2-one (1a, R1 = H). Data

25 spectroscopic as in Example 34, Method 1.

Method 3

(R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl) (1.0 g, 2.7 millimoles) dissolves

30 in 10 ml of ethanol, add concentrated H2SO4 (1 milliliter), and reflux under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, and concentrated in vacuo; the residue is dissolved in 20 ml of toluene, the organic phase is washed with a saturated aqueous solution of Na2SO3, an aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, and the solvent is evaporated in vacuo; The residue is purified by column chromatography to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-pyrrolidin-2-one (1a, R1

35 = H). Spectroscopic data as in Example 34, Method 1.

Method 4

(R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl) (1.0 g, 2.7 millimoles) dissolves

40 in 10 ml of acetic acid, add 1 milliliter of water, and reflux under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, and concentrated in vacuo; the residue is dissolved in 20 ml of toluene, washed with a saturated aqueous solution of Na2SO3, an aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, and the solvent is evaporated in vacuo; The residue is purified by column chromatography to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-pyrrolidin-2-one (1a, R1 = H). Data

45 spectroscopic as in Example 34, Method 1.

Method 5

(R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl) (1.0 g, 2.7 millimoles) dissolves

50 in 10 ml of trifluoroacetic acid, add 1 milliliter of water, and reflux under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, and concentrated in vacuo; the residue is dissolved in 20 ml of toluene, washed with a saturated aqueous solution of Na2SO3, an aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, and the solvent is evaporated in vacuo; the residue is purified by

E11734379

10-19-2015

Column chromatography to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-pyrrolidin-2-one (1a, R1 = H). Spectroscopic data as in Example 34, Method 1.

Method 5

5 (R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl) (1.0 g, 2, 7 mmol) is dissolved in 10 ml of trifluoroacetic acid, 1 milliliter of water is added, and refluxed under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, and concentrated in vacuo; the residue is dissolved in 20 ml of toluene, washed with a saturated aqueous solution of Na2SO3, an aqueous solution of Na2CO3

10 and brine, dry over anhydrous Na2SO4, and evaporate the solvent in vacuo; The residue is purified by column chromatography to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-pyrrolidin-2-one (1a, R1 = H). Spectroscopic data as in Example 34, Method 1.

Method 6

15 To a solution of (R) -5-biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl) (1.0 g, 2.7 mmol) in 10 ml of tetrahydrofuran, add 1 milliliter of methanesulfonic acid and 1 milliliter of water, and reflux under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, and concentrated in vacuo; the residue is dissolved in 20 ml of toluene, washed with an aqueous solution

20 saturated Na2SO3, an aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, and the solvent evaporated in vacuo; The residue is purified by column chromatography to obtain (R) -5-biphenyl-4-yl-methyl-3-methylene-pyrrolidin-2-one (1a, R1 = H). Spectroscopic data as in Example 34, Method 1.

Method 7

25 (R) -5-Biphenyl-4-yl-methyl-3-methylene-1 - ((E) -styryl) -pyrrolidin-2-one (1a, R1 = styryl) (10.0 g, 27 mmol ) is dissolved in 30 ml of anhydrous toluene, TsOH * H2O (6.2 g, 32.4 mmol) is added, and refluxed under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, 100 ml of toluene are added, the organic phase is washed with a saturated aqueous solution of Na2SO3, an aqueous solution of Na2CO3 and

30 brine, dry over anhydrous Na2SO4, and evaporate the solvent in vacuo, to obtain the crude product, which is recrystallized from toluene / tert-butyl-methyl-ether = from 1: 3 to approximately 1: 4, to give (R) -5-biphenyl-4-ylmethyl-3-methylene-pyrrolidin-2-one (1a, R1 = H). Spectroscopic data as in Example 34, Method 1. HPLC method (Methods 1-7) Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B

35 (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC. Holding time:

6.7 min (1a, R1 = H). 40 Example 35: (R) -5-Biphenyl-4-yl-4-tert-butoxy-carbonyl-amino-2-methylene-pentanoic acid

image129

45 Method 1

Under N2 atmosphere, add n-butyllithium (56 ml, 2.5 M in hexane, 0.14 mol) to the mixture of HMDS (24.2 g, 0.15 mol) in 300 ml of dry tetrahydrofuran at -10 ° C, and the resulting mixture is then stirred for 30 min at 10 ° C. A mixture of (S) -2-biphenyl-4-yl-methyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3a, R1 = 50 t-butoxycarbonyl) (35.1 g 0.1 mol) in 50 ml of dry tetrahydrofuran to the reaction mixture at -10 ° C; after about 30 min, n-butyllithium (40 ml, 2.5 M in hexane, 0.1 mol) is added to the reaction mixture at 10 ° C, and the resulting mixture is then stirred for 30 min at - 10 ° C. Benzoyl chloride (15.5 g, 0.11 mol) is added to the reaction mixture at -10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 100 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. Formaldehyde (37% in water, 24.3 g, 0.3 mol), an aqueous solution of K2CO3 (27.6 grams in 100 ml of water, 0.2 mol), and a solution of tetrabutylammonium hydroxide are added. (40% in water, 1.3 g, 5 mmol) to the remaining organic phase, and heated to 50 ° C, and stirred for 2 hours. Then the reaction mixture is diluted with 100 ml of brine, and stirred for 15 min, the mixture is stopped.

E11734379

10-19-2015

stirring, and the lower aqueous layer is removed. A solution of lithium hydroxide monohydrate (15 grams in 100 ml of water, 0.36 mole), and tetrabutyl ammonium bromide (0.32 g, 1 millimole) are added to the remaining organic phase, and stirred at room temperature for 2 hours. Then, approximately 50 grams of 85% phosphoric acid are added, in order to set the pH at 3.0-4.0. Then 100 ml of toluene and 100 ml of brine are added. After phase separation, it is concentrated in vacuo. The residue is dissolved in 200 ml of acetonitrile at 80 ° C, filtered hot (80 ° C) to remove the inorganic salt, and cooled to 0 ° C, while crystallization occurs, and is left to stand for 3 hours; The crystals are collected by filtration, washed with 50 ml of acetonitrile, and dried under vacuum at 50 ° C, to provide (R) -5-biphenyl-4-yl-4-tert-butoxycarbonyl-amino-2-methylene-acid. pentanoic. ¹H NMR (400 MHz, DMSO): 1.27 (s, 9H, (CH3) 3), 2.26 (m, 1H, 3-CHH), 2.49 (m,

10 1H, 3CHH), 2.71 (d, 1H, 5-CH2), 3.85 (m, 1H, 4-CH), 5.60 (s, 1H, C = CHH), 6.05 (s , 1H, C = CHH), 6.65 (d, 1H, NH), 7.20 ~ 7.70 (9H, m, aromatic), 12.34 (s, 1H, COOH). The ratio of Intermediate (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) to (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) is 70: 30, as determined by HPLC. Spectroscopic data as in Example 35, Method 1.

15 Method 2

Under N2 atmosphere, n-butyllithium (56 ml, 2.5 M in hexane, 0.14 mol) is added to the di-isopropylamine mixture (14.2 g, 0.15 mol) in 300 ml of dry tetrahydrofuran at -10 ° C, and the resulting mixture is then stirred for 30 min at -10 ° C. A mixture of (S) -2-biphenyl-4-yl-methyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester 20 (3a, R1 = t-butoxycarbonyl) (35.1 g 0.1 mol) in 50 ml of dry tetrahydrofuran to the reaction mixture at -10 ° C; after about 30 min, n-butyllithium (40 ml, 2.5 M in hexane, 0.1 mol) is added to the reaction mixture at -10 ° C, and the resulting mixture is then stirred for 30 min at -10 ° C. Benzoyl chloride (15.5 g, 0.11 mol) is added to the reaction mixture at -10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 100 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. Formaldehyde (37% in water, 24.3 g, 0.3 mol), an aqueous solution of K2CO3 (27.6 grams in 100 ml of water, 0.2 mol), and a tetrabutyl hydroxide solution are added. -ammonium (40% in water, 1.3 g, 5 mmol) to the remaining organic phase, and heated to 50 ° C, and stirred for 2 hours. The reaction mixture is then diluted with 100 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. A solution of lithium hydroxide monohydrate (15 grams in 100 ml of water, 0.36 mol), and tetrabutyl ammonium bromide (0.32 g, 1 millimole) are added to the remaining organic phase, stirred at room temperature for 2 hours. Then, approximately 50 grams of 85% phosphoric acid are added, in order to set the pH at 3.0-4.0. Then 100 ml of toluene and 100 ml of brine are added. After phase separation, it is concentrated in vacuo. The residue is dissolved in 200 ml of acetonitrile at 80 ° C, filtered hot (80 ° C) to remove the inorganic salt, and cooled to 0 ° C, while

35 shows crystallization, and is left to stand for 3 hours; The crystals are collected by filtration, washed with 50 ml of acetonitrile, and dried under vacuum at 50 ° C, to provide (R) -5-biphenyl-4-yl-4-tert-butoxycarbonyl-amino-2-methylene-acid. pentanoic. The ratio of Intermediate (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) to (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) is 70: 30, as determined by HPLC. Spectroscopic data as in Example 35, Method 1.

40 Method 3

Under N2 atmosphere, LHMDS (25 ml, 1.0 M in tetrahydrofuran, 25 mmol) is added to the mixture of (S) -2-biphenyl-4-yl-methyl-5-oxo-pyrrolidine acid tert-butyl ester. -1-carboxylic (3a, R1 = t-butoxycarbonyl) (3.51 g, 10 mmol) in 45 ml of dry tetrahydrofuran, and added to the reaction mixture at -10 ° C, and the resulting mixture was then stir for 30 min at -10 ° C. Benzoyl chloride (1.55 g, 11 mmol) is added to the reaction mixture at -10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 15 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. Formaldehyde (37% in water, 2.43 g, 0.03 mol), an aqueous solution of K2CO3 (2.76 50 grams in 10 ml of water, 0.02 mol), and a solution of hydroxide of tetrabutyl ammonium (40% in water, 0.13 g, 0.5 mmol) to the remaining organic phase, and heat to 50 ° C, and stir for 2 hours. The reaction mixture is then diluted with 15 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. Add a solution of lithium hydroxide monohydrate (1.5 grams in 10 ml of water, 0.036 mol), and tetrabutyl ammonium bromide (32 mg, 0.1 mmol) to the remaining organic phase, and stir at room temperature for 2 hours. Then, about 5 grams of 85% phosphoric acid are added, in order to set the pH at 3.0-4.0. Then 15 ml of toluene and 15 ml of brine are added. After phase separation, it is concentrated in vacuo. The residue is dissolved in 20 ml of acetonitrile at 80 ° C, filtered hot (80 ° C) to remove the inorganic salt, and cooled to 0 ° C, while crystallization occurs, and is left to stand for 3 hours; the crystals are collected by filtration, washed with 5 ml of acetonitrile, and dried under vacuum at 50 ° C, to provide (R) -5-biphenyl-4-yl-4-tert-butoxy-carbonyl-amino-2 acid. -methylene-pentanoic. The ratio of Intermediate (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) to (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) is 70: 30, as determined by HPLC. Spectroscopic data as in Example 35, Method

1.

65

E11734379

10-19-2015

Method 4

Under N2 atmosphere, add LDA (25 ml, 1.0 M in tetrahydrofuran, 25 mmol) to the mixture of (S) -2-biphenyl-4-yl-methyl-5-oxo-pyrrolidine acid tert-butyl ester. -1-carboxylic (3a, R1 = t-butoxycarbonyl) (3.51 g, 10 mmol) in 20 ml

5 of dry tetrahydrofuran, and added to the reaction mixture at -10 ° C, and the resulting mixture was then stirred for 30 min at -10 ° C. Benzoyl chloride (1.55 g, 11 mmol) is added to the reaction mixture at -10 ° C; After about 1 hour at -10 ° C, the reaction mixture is diluted with 15 ml of a saturated aqueous ammonium chloride solution, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed.

10 Formaldehyde (37% in water, 2.43 g, 0.03 mol), an aqueous solution of K2CO3 (2.76 grams in 10 ml of water, 0.02 mol), and a solution of hydroxide of tetrabutyl ammonium (40% in water, 0.13 g, 0.5 mmol) to the remaining organic phase, and heat to 50 ° C, and stir for 2 hours. The reaction mixture is then diluted with 15 ml of brine, and stirred for 15 min, stirring is discontinued, and the lower aqueous layer is removed. I know

15 Add a solution of lithium hydroxide monohydrate (1.5 grams in 10 ml of water, 0.036 mol), and tetrabutyl ammonium bromide (32 mg, 0.1 mmol) to the remaining organic phase, and stir at room temperature for 2 hours. Then, about 5 grams of 85% phosphoric acid are added, in order to set the pH at 3.0-4.0. Then 15 ml of toluene and 15 ml of brine are added. After phase separation, it is concentrated in vacuo. The residue is dissolved in 20 ml of acetonitrile at 80 ° C, filtered hot (80 ° C) to remove the

20 inorganic salt, and it is cooled to 0 ° C, while crystallization occurs, and it is left to stand for 3 hours; the crystals are collected by filtration, washed with 5 ml of acetonitrile, and dried under vacuum at 50 ° C, to provide (R) -5-biphenyl-4-yl-4-tert-butoxy-carbonyl-amino-2- acid. methylene-pentanoic. The ratio of Intermediate (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) to (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) is 70: 30, as determined by HPLC. Spectroscopic data as in Example 35, Method 1.

25 Method 5

Under N2 atmosphere, to a 1-liter flask, add the tert-butyl-ester of (S) -2-biphenyl-4-yl-methyl-5-oxopyrrolidine-1-carboxylic acid (3a, R1 = t-butoxy -carbonyl) (40 g, 159 mmol), and DMAP (2.43 g, 20 mmol), followed by

500 ml of toluene and triethylamine (26.1 g, 258 mmol). The mixture is heated to 65 ° C, diterbutyl dicarbonate (48.6 g, 223 mmol) is added over 30 min, and then stirred for 2 hours. The reaction mixture is cooled to 25 ° C, washed with 200 ml of water three times, and then concentrated. The residue is dissolved in 400 ml of tetrahydrofuran, and MgCl2 (18.0 g, 159 mmol), and triethylamine (26.1 g, 258 mmol) are added. The reaction mixture is cooled to 5 ° C, and benzoyl chloride (36.4 g, 259 mmol) is slowly added dropwise; after

After the addition, the mixture is stirred at 5 ° C for 1 hour, then heated to 10 ° C, and stirred for 15 hours. 100 ml of water are added, followed by a solution of H3PO4 (57.4 g, 510 mol) in water (100 ml). After 10 min, the aqueous phase is removed, and the organic phase is washed with brine (200 ml) twice. To the organic extracts are added a solution of potassium carbonate (65.4 g, in 200 ml of water), N-methyl-imidazole (32.6 g, 398 mmol), a solution of tetrabutyl-ammonium hydroxide ( 3.68 g, 40% w / w, 5.7 mmol), and a

40 solution of formaldehyde in water (48.4 g, 37% w / w, 613 mmol). This mixture is heated to 55 ° C, and stirred for 20 hours. After this time, the reaction temperature is cooled to 25 ° C, and the aqueous phase is removed. The organic phase is washed with saturated sodium chloride (200 ml) twice. A solution of lithium hydroxide monohydrate (29.3 grams in 200 ml of water, 698 mmol), and tetrabutyl ammonium bromide (0.65 g, 2 mmol) are added. The mixture is stirred at 25 ° C for 4 hours. Then phosphoric acid (97.6 g, 85%

45 w / w) to the reaction mixture, the pH is adjusted to 4-5 at 10 ° C to 20 ° C. The aqueous phase is removed, and a saturated solution of sodium chloride in water (200 ml) is added. The organic phase is separated and concentrated. The residue is dissolved in ethyl acetate (500 ml), and then removed in vacuo. Ethyl acetate (1000 ml) and water (400 ml) are added. The organic phase is separated, washed with water (400 ml) three times, and concentrated. To the resulting residue, toluene (400 ml) is added, and then it is removed in vacuo. Acetonitrile (400 ml) is added. The reaction mixture is put into

50 reflux and cool in about 2 hours to 4 ° C. The resulting solid is separated by filtration. The filter cake is washed with cold acetonitrile (50 ml), followed by heptane (100 ml), and dried to give (R) -5-biphenyl-4-yl-4-tert-butoxy-carbonyl-amino-2-methylene acid. -pentanoic as a white solid. The ratio of Intermediate (3S, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) to (3R, 5S-4, R1 = t-butoxycarbonyl, R4 = phenyl) is 70: 30, as determined by HPLC. Spectroscopic data as in Example 35, Method 1.

55 HPLC method (Methods 1-5) Column: Eclipse XDB-C18; 150 x 4.6 mm; 5 µm. Mobile phase A (0.1% H3PO4) in water; Mobile phase B (Acetonitrile). Gradient: 0 min (30% B); 8 min (95% of B); 15 min (95% of B). Flow rate: 1.0 ml min-1. Wavelength: 210 nm. Temperature: 30 ºC. Holding time:

60 8.0 min, (R) -5-Biphenyl-4-yl-4-tertbutoxy-carbonyl-amino-2-methylene-pentanoic acid

Claims (8)

1. A process for the preparation of a compound of formula (1), or a salt thereof, image 1 R1 5 (1) wherein R1 is hydrogen or a nitrogen protecting group; said process comprising the steps of (i) preparing a compound of formula (4), or a salt thereof, image2

R1

(4)

fifteen

wherein: R1 is hydrogen or a nitrogen protecting group; and R4 is selected from alkyl, aryl, and aryl-alkyl;

twenty

by reacting a compound of the formula (3), or a salt thereof:

image3 R1 (3) wherein R1 is hydrogen or a nitrogen protecting group; first with a base and then with a compound of the formula R4COY, wherein R4 is selected from alkyl, aryl, and aryl-alkyl, and Y is halogen or -OR ', where R' is selects from alkyl, aryl, and aryl-alkyl, to obtain the compound of the formula (4), or a salt thereof; and (ii) reacting the obtained compound of formula (4), or a salt thereof, 30 with a base and formaldehyde, optionally in the presence of a phase transfer catalyst, to obtain the compound of formula (1), or a salt thereof. 2. A process for the preparation of a compound of the formula (1), or a salt thereof, image4 R1 (1) wherein R1 is hydrogen or a nitrogen protecting group; understanding said process the steps of (i) preparing a compound of the formula (4), or a salt thereof, image5 R1 10 (4) wherein R1 is hydrogen or a nitrogen protecting group; and R4 is hydroxyl; by reacting a compound of the formula (3), or a salt thereof: image6 R1 15 (3) wherein R1 is hydrogen or a nitrogen protecting group; first with a base and then with a compound of the formula CO2 to obtain the compound of the formula (4), or a salt thereof; and (Ii) reacting the compound of formula (4) obtained, or a salt thereof, with a base and formaldehyde, optionally in the presence of a phase transfer catalyst, to obtain the compound of formula (1), or a salt thereof. A process according to claims 1 or 2, wherein the compound of formula (3) is of formula (3a): image7 R1 (3rd) wherein R1 is as defined for the compound of formula (3); the compound of formula (4) is of formula (4a): image8 R1 (4th) wherein R1 and R4 are as defined for the compound of formula (4); and wherein the compound of formula (1) is of formula (1a): image9 R1 (1a) where R1 is as defined for the compound of formula (1). The process according to any one of claims 1 to 3, wherein in step (i) the base is selected from: -a metal hydride; - an alkali metal alkoxide; 20 -an amine, optionally in the presence of an additive selected from a metal halide alkaline earth; - a base of the formula MRa, where M is an alkali metal, and Ra is alkyl or aryl; -a base of the formula RcRdNM, where Rc and Rd are independently selected from alkyl, cycloalkyl, heterocyclyl, or silyl, and M is an alkali metal; and 25 -mixtures thereof. 5. The process according to any one of claims 1 to 4, wherein in step (ii) the base is selected from: 30 -a metal hydride; -an amine; -an inorganic base; - a base of the formula MRa, where M is an alkali metal, and Ra is alkyl or aryl; - a base of the formula RcRdNM, where Rc and Rd are independently selected from alkyl, cycloalkyl, heterocyclyl or silyl, and M is an alkali metal; and - mixtures thereof. The process according to any one of claims 1 to 5, wherein in step (ii) the reaction further comprises adding an alkali metal salt and optionally a drying agent. 7. The process according to any one of claims 1 to 6, wherein steps (i) and (ii) take place through a single reaction. 10 8. The process according to any one of claims 1 to 7, wherein: R1 is selected from t-butoxy-carbonyl, benzoyl, styryl, 1-butenyl, benzyl, p-methoxy-benzyl, and pyrrolidinyl-methyl; and R4 is selected from t-butyl, methyl, isopropyl, and phenyl. 9. A compound of the formula (4), or a salt thereof: image10 20 where: R1 is hydrogen or a nitrogen protecting group selected from t-butoxy-carbonyl, benzoyl, styryl, 1-butenyl, benzyl, p-methoxy-benzyl, and pyrrolidinyl-methyl; and R4 is selected from t-butyl, methyl, isopropyl, and phenyl. 10. A compound of the formula (4) according to claim 9, wherein the compound of the formula (4) is of the formula (4a): image11 R1 30 (4th) wherein R1 and R4 are as defined for the compound of formula (4). 11. The use of a compound according to any one of claims 9 to 10 in the synthesis of a 35 NEP inhibitor or a pro-drug thereof, wherein the NEP inhibitor is N- (3-carboxy-1-oxo-propyl) (4S) -p-phenyl-phenyl-methyl) -4-amino acid - (2R) -methyl-butanoic acid or a salt thereof, and the NEP inhibitor pro-drug is N- (3-carboxyl-1-oxo-propyl) - (4S) - (p- phenyl-phenyl-methyl) -4-amino- (2R) -methyl-butanoic acid or a salt thereof. The process according to any one of claims 1 to 8 further comprising the step of preparing N- (3-carboxyl-1-oxo-propyl) - (4S) - (p-phenyl acid ethyl ester -phenyl-methyl) -4-amino- (2R) -methyl-butanoic acid, or a salt thereof.